U.S. Department of Health and Human Services s6

Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention (CDC) Atlanta, GA 30333 June 29, 2001 / Vol. 50 / No. RR-11 Recommendations and Reports The MMWR series of publications is published by the Epidemiology Program Office, Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333.

SUGGESTED CITATION Centers for Disease Control and Prevention. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR 2001;50(No. RR-11): [inclusive page numbers].

Centers for Disease Control and Prevention...... Jeffrey P. Koplan, M.D., M.P.H. Director

The material in this report was prepared for publication by National Center for Infectious Diseases ...... James H. Hughes, M.D. Director

Division of Healthcare Quality Promotion...... Julie L. Gerberding, M.D., M.P.H. Director

Division of Viral Hepatitis (Proposed) ...... Harold S. Margolis, M.D. Acting Director

Division of AIDS, STD, and TB Laboratory Research...... Harold W. Jaffe, M.D. Director

National Center for HIV, STD, and TB Prevention ...... Helene D. Gayle, M.D., M.PH. Director

Division of HIV/AIDS Prevention — Surveillance and Epidemiology ...... Robert S. Janssen, M.D. Director

National Institute for Occupational Safety and Health...... Kathleen Rest, Ph.D. Acting Director

Division of Surveillance, Hazard Evaluations, and Field Studies...... R. Delon Hull, Ph.D. Acting Director

This report was produced as an MMWR serial publication in Epidemiology Program Office ...... Stephen B. Thacker, M.D., M.Sc. Director

Office of Scientific and Health Communications...... John W. Ward, M.D. Director Editor, MMWR Series

CDC Surveillance Summaries...... Suzanne M. Hewitt, M.P.A. Managing Editor

...... Patricia A. McGee Project Editor

...... Lynda G. Cupell and Morie M. Higgins Visual Information Specialists Michele D. Renshaw and Erica R. Shaver Information Technology Specialists Contents Summary ...... 1 Introduction ...... 1 Definition of Health-Care Personnel and Exposure...... 2 Background ...... 3 Occupational Transmission of HBV...... 3 Occupational Transmission of HCV...... 5 Occupational Transmission of HIV ...... 6 Recommendations for the Management of HCP Potentially Exposed to HBV, HCV, or HIV ...... 14 Hepatitis B Vaccination...... 14 Treatment of an Exposure Site ...... 15 Exposure Report...... 15 Evaluation of the Exposure and the Exposure Source...... 15 Management of Exposures to HBV ...... 18 Management of Exposures to HCV ...... 18 Management of Exposures to HIV...... 19 Recommendations for the Selection of Drugs for HIV PEP...... 24 Occupational Exposure Management Resources...... 27 References ...... 29 Appendices ...... 39 Continuing Education Examination ...... CE-1 The following CDC staff members prepared this report:

Elise M. Beltrami, M.D. Francisco Alvarado-Ramy, M.D. Sara E. Critchley, R.N. Adelisa L. Panlilio, M.D., M.P.H. Denise M. Cardo, M.D. Division of Healthcare Quality Promotion National Center for Infectious Diseases

William A. Bower, M.D. Miriam J. Alter, Ph.D. Division of Viral Hepatitis* National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases and Division of HIV/AIDS Prevention National Center for HIV, STD, and TB Prevention

Boris Lushniak, M.D., M.P.H. Division of Surveillance, Hazard Evaluations, and Field Studies National Institute for Occupational Safety and Health

in collaboration with

David K. Henderson, M.D. National Institutes of Health

Kimberly A. Struble, Pharm.D. Food and Drug Administration

Abe Macher, M.D. Health Resources and Services Administration Vol. 50/No. RR-11 MMWR 1

Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis Summary

This report updates and consolidates all previous U.S. Public Health Service recommendations for the management of health-care personnel (HCP) who have occupational exposure to blood and other body fluids that might contain hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Recommendations for HBV postexposure management include initiation of the hepatitis B vaccine series to any susceptible, unvaccinated person who sustains an occupational blood or body fluid exposure. Postexposure prophylaxis (PEP) with hepatitis B immune globulin (HBIG) and/or hepatitis B vaccine series should be considered for occupational exposures after evaluation of the hepatitis B surface antigen status of the source and the vaccination and vaccine-response status of the exposed person. Guidance is provided to clinicians and exposed HCP for selecting the appropriate HBV PEP. Immune globulin and antiviral agents (e.g., interferon with or without ribavirin) are not recommended for PEP of hepatitis C. For HCV postexposure management, the HCV status of the source and the exposed person should be determined, and for HCP exposed to an HCV positive source, follow-up HCV testing should be performed to determine if infection develops. Recommendations for HIV PEP include a basic 4-week regimen of two drugs (zidovudine [ZDV] and lamivudine [3TC]; 3TC and stavudine [d4T]; or didanosine [ddI] and d4T) for most HIV exposures and an expanded regimen that includes the addition of a third drug for HIV exposures that pose an increased risk for transmission. When the source person’s virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person’s virus is unlikely to be resistant is recommended. In addition, this report outlines several special circumstances (e.g., delayed exposure report, unknown source person, pregnancy in the exposed person, resistance of the source virus to antiretroviral agents, or toxicity of the PEP regimen) when consultation with local experts and/or the National Clinicians’ Post- Exposure Prophylaxis Hotline ([PEPline] 1-888-448-4911) is advised. Occupational exposures should be considered urgent medical concerns to ensure timely postexposure management and administration of HBIG, hepatitis B vaccine, and/or HIV PEP.

INTRODUCTION

Avoiding occupational blood exposures is the primary way to prevent transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in health-care settings (1 ). However, hepatitis B immunization and postexposure management are integral components of a complete program to prevent infection following bloodborne pathogen exposure and are important elements of workplace safety (2 ). The U.S. Public Health Service (PHS) has published previous guidelines for the management of HIV exposures that included considerations for postexposure prophylaxis (PEP) (3–5 ). Since publication of the 1998 HIV exposure guidelines (5 ), several new antiretroviral agents have been approved by the Food and Drug Administration (FDA), and more information is available about the use and safety of HIV PEP (6–11 ). In addition, questions exist regarding considerations about PEP regimens when the source person’s virus is known or suspected to be resistant to one or more of the antiretroviral agents that might be used for PEP. Concern also has arisen about the use of PEP when it is not warranted. Data indicate that some health-care personnel (HCP) take a full course of HIV PEP after exposures that do not confer an HIV transmission risk (10,11 ). 2 MMWR June 29, 2001

In September 1999, a meeting of a PHS interagency working group* and expert consultants was convened by CDC. The PHS working group decided to issue updated recommendations for the management of occupational exposure to HIV. In addition, the report was to include recommendations for the management of occupational HBV and HCV exposures so that a single document could comprehensively address the management of occupational exposures to bloodborne pathogens. This report updates and consolidates the previous PHS guidelines and recommendations for occupational HBV, HCV, and HIV exposure management for HCP. Specific practice recommendations for the management of occupational bloodborne pathogen exposures are outlined to assist health-care institutions with the implementation of these PHS guidelines (Appendices A and B). As relevant information becomes available, updates of these recommendations will be published. Recommendations for nonoccupational (e.g., sexual, pediatric, and perinatal) HBV, HCV, and HIV exposures are not addressed in these guidelines and can be found elsewhere (12–15 ).

Definition of Health-Care Personnel and Exposure

In this report, health-care personnel (HCP) are defined as persons (e.g., employees, students, contractors, attending clinicians, public-safety workers, or volunteers) whose activities involve contact with patients or with blood or other body fluids from patients in a health-care, laboratory, or public- safety setting. The potential exists for blood and body fluid exposure to other workers, and the same principles of exposure management could be applied to other settings.

*This interagency working group comprised representatives of CDC, the Food and Drug Administration (FDA), the Health Resources and Services Administration, and the National Institutes of Health. Information included in these recommendations may not represent FDA approval or approved labeling for the particular product or indications in question. Specifically, the terms “safe” and “effective” may not be synonymous with the FDA-defined legal standards for product approval. An exposure that might place HCP at risk for HBV, HCV, or HIV infection is defined as a percutaneous injury (e.g., a needlestick or cut with a sharp object) or contact of mucous membrane or nonintact skin (e.g., exposed skin that is chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other body fluids that are potentially infectious (16,17 ). In addition to blood and body fluids containing visible blood, semen and vaginal secretions also are considered potentially infectious. Although semen and vaginal secretions have been implicated in the sexual transmission of HBV, HCV, and HIV, they have not been implicated in occupational transmission from patients to HCP. The following fluids also are considered potentially infectious: cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid. The risk for transmission of HBV, HCV, and HIV infection from these fluids is unknown; the potential risk to HCP from occupational exposures has not been assessed by epidemiologic studies in health-care settings. Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they contain blood. The risk for transmission of HBV, HCV, and HIV infection from these fluids and materials is extremely low. Any direct contact (i.e., contact without barrier protection) to concentrated virus in a research laboratory or production facility is considered an exposure that requires clinical evaluation. For human bites, the clinical evaluation must include the possibility that both the person bitten and the person who inflicted the bite were exposed to bloodborne pathogens. Transmission of HBV or HIV infection only rarely has been reported by this route (18–20 ) (CDC, unpublished data, 1998). Vol. 50/No. RR-11 MMWR 3

BACKGROUND This section provides the rationale for the postexposure management and prophylaxis recommendations presented in this report. Additional details concerning the risk for occupational bloodborne pathogen transmission to HCP and management of occupational bloodborne pathogen exposures are available elsewhere (5,12,13,21-24 ).

Occupational Transmission of HBV Risk for Occupational Transmission of HBV

HBV infection is a well recognized occupational risk for HCP (25 ). The risk of HBV infection is primarily related to the degree of contact with blood in the work place and also to the hepatitis B e antigen (HBeAg) status of the source person. In studies of HCP who sustained injuries from needles contaminated with blood containing HBV, the risk of developing clinical hepatitis if the blood was both hepatitis B surface antigen (HBsAg)- and HBeAg-positive was 22%–31%; the risk of developing serologic evidence of HBV infection was 37%–62%. By comparison, the risk of developing clinical hepatitis from a needle contaminated with HBsAg-positive, HBeAg-negative blood was 1%–6%, and the risk of developing serologic evidence of HBV infection, 23%–37% (26 ). Although percutaneous injuries are among the most efficient modes of HBV transmission, these exposures probably account for only a minority of HBV infections among HCP. In several investigations of nosocomial hepatitis B outbreaks, most infected HCP could not recall an overt percutaneous injury (27,28 ), although in some studies, up to one third of infected HCP recalled caring for a patient who was HBsAg-positive (29,30 ). In addition, HBV has been demonstrated to survive in dried blood at room temperature on environmental surfaces for at least 1 week (31 ). Thus, HBV infections that occur in HCP with no history of nonoccupational exposure or occupational percutaneous injury might have resulted from direct or indirect blood or body fluid exposures that inoculated HBV into cutaneous scratches, abrasions, burns, other lesions, or on mucosal surfaces (32– 34 ). The potential for HBV transmission through contact with environmental surfaces has been demonstrated in investigations of HBV outbreaks among patients and staff of hemodialysis units (35–37 ). Blood contains the highest HBV titers of all body fluids and is the most important vehicle of transmission in the health-care setting. HBsAg is also found in several other body fluids, including breast milk, bile, cerebrospinal fluid, feces, nasopharyngeal washings, saliva, semen, sweat, and synovial fluid (38 ). However, the concentration of HBsAg in body fluids can be 100–1000—fold higher than the concentration of infectious HBV particles. Therefore, most body fluids are not efficient vehicles of transmission because they contain low quantities of infectious HBV, despite the presence of HBsAg. In serologic studies conducted in the United States during the 1970s, HCP had a prevalence of HBV infection approximately 10 times higher than the general population (39–42 ). Because of the high risk of HBV infection among HCP, routine preexposure vaccination of HCP against hepatitis B and the use of standard precautions to prevent exposure to blood and other potentially infectious body fluids have been recommended since the early 1980s (43 ). Regulations issued by the Occupational Safety and Health Administration (OSHA) (2 ) have increased compliance with these recommendations. Since the implementation of these recommendations, a sharp decline has occurred in the incidence of HBV infection among HCP.

PEP for HBV

Efficacy of PEP for HBV. The effectiveness of hepatitis B immune globulin (HBIG) and/ or hepatitis B vaccine in various postexposure settings has been evaluated by prospective studies. For perinatal exposure to an HBsAg-, HBeAg-positive mother, a regimen combining HBIG and initiation of the hepatitis B vaccine series at birth is 85%–95% effective in preventing HBV infection (44,45 ). Regimens involving either multiple doses of HBIG alone or the hepatitis B vaccine series alone are 4 MMWR June 29, 2001 70%–75% effective in preventing HBV infection (46 ). In the occupational setting, multiple doses of HBIG initiated within 1 week following percutaneous exposure to HBsAg-positive blood provides an estimated 75% protection from HBV infection (47–49 ). Although the postexposure efficacy of the combination of HBIG and the hepatitis B vaccine series has not been evaluated in the occupational setting, the increased efficacy of this regimen observed in the perinatal setting, compared with HBIG alone, is presumed to apply to the occupational setting as well. In addition, because persons requiring PEP in the occupational setting are generally at continued risk for HBV exposure, they should receive the hepatitis B vaccine series. Safety of PEP for HBV. Hepatitis B vaccines have been found to be safe when administered to infants, children, or adults (12,50 ). Through the year 2000, approximately 100 million persons have received hepatitis B vaccine in the United States. The most common side effects from hepatitis B vaccination are pain at the injection site and mild to moderate fever (50–55 ). Studies indicate that these side effects are reported no more frequently among persons vaccinated than among those receiving placebo (51,52 ). Approximately 45 reports have been received by the Vaccine Adverse Event Report- ing System (VAERS) of alopecia (hair loss) in children and adults after administration of plasma-derived and recombinant hepatitis B vaccine; four persons sustained hair loss following vaccination on more than one occasion (56 ). Hair loss was temporary for approximately two thirds of persons who experienced hair loss. An epidemiologic study conducted in the Vaccine Safety Datalink found no statistical association between alopecia and receipt of hepatitis B vaccine in children (CDC, unpublished data, 1998). A low rate of anaphylaxis has been observed in vaccine recipients based on reports to VAERS; the estimated incidence is 1 in 600,000 vaccine doses distributed. Although none of the persons who developed anaphylaxis died, anaphylactic reactions can be life-threatening; therefore, further vaccination with hepatitis B vaccine is contraindicated in persons with a history of anaphylaxis after a previous dose of vaccine. Hepatitis B immunization programs conducted on a large scale in Taiwan, Alaska, and New Zealand have observed no association between vaccination and the occurrence of serious adverse events. Furthermore, in the United States, surveillance of adverse events following hepatitis B vaccination has demonstrated no association between hepatitis B vaccine and the occurrence of serious adverse events, including Guillain-Barré syndrome, transverse myelitis, multiple sclerosis, optic neuritis, and seizures (57–59 ) (CDC, unpublished data, 1991). However, several case reports and case series have claimed an association between hepatitis B vaccination and such syndromes and diseases as multiple sclerosis, optic neuritis, rheumatoid arthritis, and other autoimmune diseases (57,60– 66 ). Most of these reported adverse events have occurred in adults, and no report has compared the frequency of the purported vaccine-associated syndrome/disease with the frequency in an unvaccinated population. In addition, recent case-control studies have demonstrated no association between hepatitis B vaccination and development or short-term risk of relapse of multiple sclerosis (67,68 ), and reviews by international panels of experts have concluded that available data do not demonstrate a causal association between hepatitis B vaccination and demyelinating diseases, including multiple sclerosis (69 ). HBIG is prepared from human plasma known to contain a high titer of antibody to HBsAg (anti- HBs). The plasma from which HBIG is prepared is screened for HBsAg and antibodies to HIV and HCV. The process used to prepare HBIG inactivates and eliminates HIV from the final product. Since 1996, the final product has been free of HCV RNA as determined by the polymerase chain reaction (PCR), and, since 1999, all products available in the United States have been manufactured by methods that inactivate HCV and other viruses. No evidence exists that HBV, HCV, or HIV have ever been transmitted by HBIG commercially available in the United States (70,71 ). Vol. 50/No. RR-11 MMWR 5

Serious adverse effects from HBIG when administered as recommended have been rare. Local pain and tenderness at the injection site, urticaria and angioedema might occur; anaphylactic reactions, although rare, have been reported following the injection of human immune globulin (IG) preparations (72 ). Persons with a history of anaphylactic reaction to IG should not receive HBIG. PEP for HBV During Pregnancy. No apparent risk exists for adverse effects to developing fetuses when hepatitis B vaccine is administered to pregnant women (CDC, unpublished data, 1990). The vaccine contains noninfectious HBsAg particles and should pose no risk to the fetus. HBV infection during pregnancy might result in severe disease for the mother and chronic infection for the newborn. Therefore, neither pregnancy nor lacta- tion should be considered a contraindication to vaccination of women. HBIG is not contraindicated for pregnant or lactating women.

Occupational Transmission of HCV

Risk for Occupational Transmission of HCV HCV is not transmitted efficiently through occupational exposures to blood. The average incidence of anti-HCV seroconversion after accidental percutaneous exposure from an HCV-positive source is 1.8% (range: 0%–7%) (73–76 ), with one study indicating that transmission occurred only from hollow-bore needles compared with other sharps (75 ). Transmission rarely occurs from mucous membrane exposures to blood, and no transmission in HCP has been documented from intact or nonintact skin exposures to blood (77,78 ). Data are limited on survival of HCV in the environment. In contrast to HBV, the epidemiologic data for HCV suggest that environmental contamination with blood containing HCV is not a significant risk for transmission in the health-care setting (79,80 ), with the possible exception of the hemodialysis setting where HCV transmission related to environmental contamination and poor infection-control practices have been implicated (81–84 ). The risk for transmission from exposure to fluids or tissues other than HCV-infected blood also has not been quantified but is expected to be low.

Postexposure Management for HCV

In several studies, researchers have attempted to assess the effectiveness of IG following possible exposure to non-A, non-B hepatitis. These studies have been difficult to interpret because they lack uniformity in diagnostic criteria and study design, and, in all but one study, the first dose of IG was administered before potential exposure (48,85,86 ). In an experiment designed to model HCV transmission by needlestick exposure in the health-care setting, high anti-HCV titer IG administered to chimpanzees 1 hour after exposure to HCV-positive blood did not prevent transmission of infection (87 ). In 1994, the Advisory Committee on Immunization Practices (ACIP) reviewed available data regarding the prevention of HCV infection with IG and concluded that using IG as PEP for hepatitis C was not supported (88 ). This conclusion was based on the following facts:  No protective antibody response has been identified following HCV infection.  Previous studies of IG use to prevent posttransfusion non-A, non-B hepatitis might not be relevant in making recommendations regarding PEP for hepatitis C.  Experimental studies in chimpanzees with IG containing anti-HCV failed to prevent transmission of infection after exposure. No clinical trials have been conducted to assess postexposure use of antiviral agents (e.g., interferon with or without ribavirin) to prevent HCV infection, and antivirals are not FDA-approved for this indication. Available data suggest that an established infection might need to be present before interferon can be an effective treatment. Kinetic studies suggest that the effect of interferon on chronic HCV infection occurs in two phases. During the first phase, interferon blocks the production or release of virus from infected cells. In the second phase, virus is eradicated from the infected cells (89 ); in this 6 MMWR June 29, 2001 later phase, higher pretreatment alanine aminotransferase (ALT) levels correlate with an increasing decline in infected cells, and the rapidity of the decline correlates with viral clearance. In contrast, the effect of antiretrovirals when used for PEP after exposure to HIV is based on inhibition of HIV DNA synthesis early in the retroviral replicative cycle. In the absence of PEP for HCV, recommendations for postexposure management are intended to achieve early identification of chronic disease and, if present, referral for evaluation of treatment options. However, a theoretical argument is that intervention with antivirals when HCV RNA first becomes detectable might prevent the development of chronic infection. Data from studies conducted outside the United States suggest that a short course of interferon started early in the course of acute hepatitis C is associated with a higher rate of resolved infection than that achieved when therapy is begun after chronic hepatitis C has been well established (90–92 ). These studies used various treatment regimens and included persons with acute disease whose peak ALT levels were 500–1,000 IU/L at the time therapy was initiated (2.6–4 months after exposure). No studies have evaluated the treatment of acute infection in persons with no evidence of liver disease (i.e., HCV RNA-positive <6 months duration with normal ALT levels); among patients with chronic HCV infection, the efficacy of antivirals has been demonstrated only among patients who also had evidence of chronic liver disease (i.e., abnormal ALT levels). In addition, treatment started early in the course of chronic HCV infection (i.e., 6 months after onset of infection) might be as effective as treatment started during acute infection (13 ). Because 15%–25% of patients with acute HCV infection spontaneously resolve their infection (93 ), treatment of these patients during the acute phase could expose them unnecessarily to the discomfort and side effects of antiviral therapy. Data upon which to base a recommendation for therapy of acute infection are insufficient because a) no data exist regarding the effect of treating patients with acute infection who have no evidence of disease, b) treatment started early in the course of chronic infection might be just as effective and would eliminate the need to treat persons who will spontaneously resolve their infection, and c) the appropriate regimen is unknown.

Occupational Transmission of HIV

Risk for Occupational Transmission of HIV In prospective studies of HCP, the average risk of HIV transmission after a percutaneous exposure to HIV-infected blood has been estimated to be approximately 0.3% (95% confidence interval [CI] = 0.2%–0.5%) (94 ) and after a mucous membrane exposure, approximately 0.09% (95% CI = 0.006%–0.5%) (95 ). Although episodes of HIV transmission after nonintact skin exposure have been documented (96 ), the average risk for transmission by this route has not been precisely quantified but is estimated to be less than the risk for mucous membrane exposures (97 ). The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified but is probably considerably lower than for blood exposures (98 ). As of June 2000, CDC had received voluntary reports of 56 U.S. HCP with documented HIV seroconversion temporally associated with an occupational HIV exposure. An additional 138 episodes in HCP are considered possible occupational HIV transmis- sions. These workers had a history of occupational exposure to blood, other infectious body fluids, or laboratory solutions containing HIV, and no other risk for HIV infection was identified, but HIV seroconversion after a specific exposure was not documented (99 ). Epidemiologic and laboratory studies suggest that several factors might affect the risk of HIV transmission after an occupational exposure. In a retrospective case-control study of HCP who had percutaneous exposure to HIV, the risk for HIV infection was found to be increased with exposure to a larger quantity of blood from the source person as indicated by a) a device visibly contaminated with the patient’s blood, b) a procedure that involved a needle being placed directly in a vein or artery, or c) a deep injury (100 ). Vol. 50/No. RR-11 MMWR 7 The risk also was increased for exposure to blood from source persons with terminal illness, possibly reflecting either the higher titer of HIV in blood late in the course of AIDS or other factors (e.g., the presence of syncytia-inducing strains of HIV). A laboratory study that demonstrated that more blood is transferred by deeper injuries and hollow-bore needles lends further support for the observed variation in risk related to blood quantity (101 ). The use of source person viral load as a surrogate measure of viral titer for assessing transmission risk has not yet been established. Plasma viral load (e.g., HIV RNA) reflects only the level of cell-free virus in the peripheral blood; latently infected cells might transmit infection in the absence of viremia. Although a lower viral load (e.g., <1,500 RNA copies/mL) or one that is below the limits of detection probably indicates a lower titer exposure, it does not rule out the possibility of transmission. Some evidence exists regarding host defenses possibly influencing the risk for HIV infection. A study of HIV-exposed but uninfected HCP demonstrated an HIV-specific cytotoxic T-lymphocyte (CTL) response when peripheral blood mononuclear cells were stimu- lated in vitro with HIV-specific antigens (102 ). Similar CTL responses have been observed in other groups who experienced repeated HIV exposure without resulting infection (103–108 ). Among several possible explanations for this observation is that the host immune response sometimes might prevent establishment of HIV infection after a percutaneous exposure; another is that the CTL response simply might be a marker for exposure. In a study of 20 HCP with occupational exposure to HIV, a comparison was made of HCP treated with zidovudine (ZDV) PEP and those not treated. The findings from this study suggest that ZDV blunted the HIV-specific CTL response and that PEP might inhibit early HIV replication (109 ).

Rationale for HIV PEP

Considerations that influence the rationale and recommendations for PEP include  the pathogenesis of HIV infection, particularly the time course of early infection;  the biological plausibility that infection can be prevented or ameliorated by using antiretroviral drugs;  direct or indirect evidence of the efficacy of specific agents used for prophylaxis; and  the risk and benefit of PEP to exposed HCP.

The following discussion considers each of these concerns.

Role of Pathogenesis in Considering Antiretroviral Prophylaxis. Information about primary HIV infection indicates that systemic infection does not occur immediately, leav- ing a brief window of opportunity during which postexposure antiretroviral intervention might modify or prevent viral replication. In a primate model of simian immunodeficiency virus (SIV) infection, infection of dendritic- like cells occurred at the site of inoculation during the first 24 hours following mucosal exposure to cell- free virus. Over the subse- quent 24–48 hours, migration of these cells to regional lymph nodes occurred, and virus was detectable in the peripheral blood within 5 days (110 ). Theoretically, initiation of antiretroviral PEP soon after exposure might prevent or inhibit systemic infection by limiting the proliferation of virus in the initial target cells or lymph nodes.

Efficacy of Antiretrovirals for PEP in Animal Studies. Data from animal studies have been difficult to interpret, in part, because of problems identifying an animal model that is comparable to humans. In early studies, differences in controlled variables (e.g., choice of viral strain [based on the animal model used], inoculum size, route of inoculation, time of prophylaxis initiation, and drug regimen) made extrapolation of the results to humans difficult. Recently, refinements in methodology have facilitated more relevant studies; in particular, the viral inocula used in animal studies have been reduced to levels more analogous to human exposures but sufficient to cause infection in control animals (111– 113 ). These studies provide encouraging evidence of postexposure chemoprophylactic efficacy. 8 MMWR June 29, 2001

Studies among primates and in murine and feline animal models have demonstrated that larger viral inocula decrease prophylactic efficacy (114–117 ). In addition, delaying initiation, shortening the duration, or decreasing the antiretroviral dose of PEP, individu- ally or in combination, decreased prophylactic efficacy (113,118–124 ). For example, when (R)-9-(2-phosphonylmethoxypropyl) adenine (tenofovir) was administered 48 hours before, 4 hours after, or 24 hours after intravenous SIV inoculation to long-tailed macaques, a 4-week regimen prevented infection in all treated animals (122 ). A subse- quent study confirmed the efficacy of tenofovir PEP when administered 24 hours after intravenous inoculation of a dose of SIV that uniformly results in infection in untreated macaques. In the same study, protection was incomplete if the tenofovir administration was delayed to 48 or 72 hours postexposure or if the total duration of treatment was curtailed to 3 or 10 days (123 ).

Efficacy of Antiretrovirals for PEP in Human Studies. Little information exists from which the efficacy of PEP in humans can be assessed. Seroconversion is infrequent following an occupational exposure to HIV-infected blood; therefore, several thousands of exposed HCP would need to enroll in a prospective trial to achieve the statistical power necessary to directly demonstrate PEP efficacy (125 ). In the retrospective case-control study of HCP, after controlling for other risk factors for HIV transmission, use of ZDV as PEP was associated with a reduction in the risk of HIV infection by approximately 81% (95% CI = 43%–94%) (100 ). Although the results of this study suggest PEP efficacy, its limitations include the small number of cases studied and the use of cases and controls from different cohorts. In a multicenter trial in which ZDV was administered to HIV-infected pregnant women and their infants, the administration of ZDV during pregnancy, labor, and delivery and to the infant reduced transmission by 67% (126 ). Only part of the protective effect of ZDV was explained by reduction of the HIV viral load in the maternal blood, suggesting that ZDV prophylaxis, in part, involves a mechanism other than the reduction of maternal viral burden (127,128 ). Since 1998, studies have highlighted the importance of PEP for prevention of perinatal HIV transmission. In Africa, the use of ZDV in combination with lamivudine (3TC) decreased perinatal HIV transmission by 50% when administered during pregnancy, labor, and for 1 week postpartum, and by 37% when started at the onset of labor and continued for 1 week postpartum (129 ). Studies in the United States and Uganda also have demonstrated that rates of perinatal HIV transmission have been reduced with the use of abbreviated PEP regimens started intrapartum or during the first 48–72 hours of life (130–132 ). The limitations of all of these studies with animals and humans must be considered when reviewing evidence of PEP efficacy. The extent to which data from animal studies can be extrapolated to humans is largely unknown, and the exposure route for mother- to-infant HIV transmission is not similar to occupational exposures; therefore, these findings might not be directly applicable to PEP in HCP.

Reports of Failure of PEP. Failure of PEP to prevent HIV infection in HCP has been reported in at least 21 instances (78,133–139 ). In 16 of the cases, ZDV was used alone as a single agent; in two cases, ZDV and didanosine (ddI) were used in combination (133,138 ); and in three cases, >3 drugs were used for PEP (137–139 ). Thirteen of the source persons were known to have been treated with antiretroviral therapy before the exposure. Antiretroviral resistance testing of the virus from the source person was performed in seven instances, and in four, the HIV infection transmitted was found to have decreased sensitivity to ZDV and/or other drugs used for PEP. In addition to possible exposure to an antiretroviral-resistant strain of HIV, other factors that might have con- tributed to these apparent failures might include a high titer and/or large inoculum exposure, delayed initiation and/or short duration of PEP, and possible factors related to the host (e.g., cellular immune system responsiveness) and/or to the source person’s virus (e.g., presence of syncytia-forming strains) (133 ). Details regarding the cases of PEP failure involving combinations of antiretroviral agents are included in this report (Table 1). Vol. 50/No. RR-11 MMWR 9

Antiretroviral Agents for PEP

Antiretroviral agents from three classes of drugs are available for the treatment of HIV infection. These agents include the nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Only antiretroviral agents that have been approved by FDA for treatment of HIV infection are discussed in these guidelines. Determining which agents and how many to use or when to alter a PEP regimen is largely empiric. Guidelines for the treatment of HIV infection, a condition usually involving a high total body burden of HIV, include recommendations for the use of three drugs (140 ); however, the applicability of these recommendations to PEP remains unknown. In HIV-infected patients, combination regimens have proved superior to monotherapy regimens in reducing HIV viral load, reducing the incidence of opportunistic infections and death, and delaying onset of drug resistance (141,142 ). A combination of drugs with activity at different stages in the viral replication cycle (e.g., nucleoside analogues with a PI) theoretically could offer an additional preventive effect in PEP, particularly for occupational exposures that pose an increased risk of transmission. Although the use of a three- drug regimen might be justified for exposures that pose an increased risk of transmission, whether the potential added toxicity of a third drug is justified for lower-risk exposures is uncertain. Therefore, the recommendations at the end of this document provide guidance for two- and three-drug PEP regimens that are based on the level of risk for HIV transmission represented by the exposure. NRTI combinations that can be considered for PEP include ZDV and 3TC, 3TC and stavudine (d4T), and ddI and d4T. In previous PHS guidelines, a combination of ZDV and 3TC was considered the first choice for PEP regimens (3 ). Because ZDV and 3TC are available in a combination formulation (Combivir™, manufactured by Glaxo Wellcome, Inc., Research Triangle Park, NC), the use of this combination might be more convenient for HCP. However, recent data suggest that mutations associated with ZDV and 3TC resistance might be common in some areas (143 ). Thus, individual clinicians might pre- fer other NRTIs or combinations based on local knowledge and experience in treating HIV infection and disease.

TABLE 1. Reported instances of failure of combination drug postexposure prophylaxis to prevent HIV infection in health-care personnel exposed to HIV-infected blood

Report Source of Regimen* Hours to Days to Days to Source no. injury first dose onset of seroconversions† patient on retroviral antiretrovirals illness 1 Biopsy needle ZDV, ddI 0.50 23 23 Yes 2 Hollow needle ZDV, ddI** 1.50 45 97 no 3¶ Large-bore 3-drugs†† 1.50 40 55 yes§§ hollow needle 4¶¶ Hollow needle ZDV, 3TC 0.67 70 83 yes*** ddI, IDV 5††† Unknown ddI, d4T 2.00 42 100 yes*** sharp NVP§§§ Vol. 50/No. RR-11 MMWR 11 *ZDV = zidovudine, ddl = didanosine, 3TC = lamivudine, IDV = indinavir, d4T = stavudine, and NVP = nevirapine

†By enzyme immunoassay for HIV-1 antibody and Western blot.

§Jochimsen EM. Failures of zidovudine postexposure prophylaxis. Am J Med 1997;102(suppl 5B):52–5.

¶Lot F, Abiteboul D. Occupational HIV infection in France [Abstract WP-25]. In: Keynote addresses and abstracts of the 4th ICOH International Conference on Occupational Health for Health Care Workers. Montreal, Canada, 1999.

** Report 2: ZDV and ddI taken for 48 hours then changed to ZDV alone.

††Report 3: ZDV, 3TC, and IDV taken for 48 hours then changed to d4T, 3TC, and IDV.

§§HIV isolate tested and determined to be sensitive to antiretroviral agent(s).

¶¶Perdue B, Wolderufael D, Mellors J, Quinn T, Margolick J. HIV-1 transmission by a needlestick injury despite rapid initiation of four-drug postexposure prophylaxis [Ab- stract 210]. In: Program and abstracts of the 6th Conference on Retroviruses and Oppor- tunistic Infections. Chicago, IL: Foundation for Retrovirology and Human Health in scientific collaboration with the National Institute of Allergy and Infectious Diseases and CDC, 1999:107.

*** HIV isolate tested and determined to be resistant to antiretroviral agent(s).

†††Beltrami EM, Luo C-C, Dela Torre N, Cardo DM. HIV transmission after an occupational exposure despite postexposure prophylaxis with a combination drug regimen [Abstract P-S2-62]. In: Program and abstracts of the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections in conjunction with the 10th Annual Meeting of SHEA. Atlanta, GA: CDC, 2000:125–6.

§§§Report 5: ZDV and 3TC taken for one dose then changed to ddI, d4T, and NVP; ddI was discontinued after 3 days because of severe vomiting.

The addition of a third drug for PEP following high-risk exposures is based on demonstrated effectiveness in reducing viral burden in HIV-infected persons. Previously, indinavir (IDV) or nelfinavir (NFV) were recommended as first-choice agents for inclusion in an expanded PEP regimen (5 ). Since the publication of the 1998 PEP guidelines, efavirenz (EFV), an NNRTI; abacavir (ABC), a potent NRTI; and Kaletra™, a PI, have been approved by FDA. Although side effects might be common with the NNRTIs, EFV might be considered for expanded PEP regimens, especially when resistance to PIs in the source person’s virus is known or suspected. ABC has been associated with dangerous hypersensitivity reactions but, with careful monitoring, may be considered as a third drug for PEP. Kaletra, a combination of lopinavir and ritonavir, is a potent HIV inhibitor that, with expert consultation, may be considered in an expanded PEP regimen.

Toxicity and Drug Interactions of Antiretroviral Agents. When administering PEP, an important goal is completion of a 4-week PEP regimen when PEP is indicated. Therefore, the toxicity profile of antiretroviral agents, including the frequency, severity, duration, and reversibility of side effects, is a relevant consideration. All of the antiretroviral agents have been associated with side effects (Table 2). However, studies of adverse events have been conducted primarily with persons who have advanced disease (and longer treatment courses) and who therefore might not reflect the experience in persons who are uninfected (144 ). Vol. 50/No. RR-11 MMWR 12

Several primary side effects are associated with antiretroviral agents (Table 2). Side effects associated with many of the NRTIs are chiefly gastrointestinal (e.g., nausea or diarrhea); however, ddI has been associated with cases of fatal and nonfatal pancreatitis among HIV-infected patients treated for >4 weeks. The use of PIs has been associated with new onset diabetes mellitus, hyperglycemia, diabetic ketoacidosis, exacerbation of preexisting diabetes mellitus, and dyslipidemia (145–147 ). Nephrolithiasis has been associated with IDV use; however, the incidence of this potential complication might be limited by drinking at least 48 ounces (1.5 L) of fluid per 24-hour period (e.g., six 8- ounce glasses of water throughout the day) (148 ). NFV has been associated with the development of diarrhea; however, this side effect might respond to treatment with antimotility agents that can be prescribed for use, if necessary, at the time the drug is recommended for PEP. The NNRTIs have been associated with severe skin reactions, including life- threatening cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hepa- totoxicity, including fatal hepatic necrosis, has occurred in patients treated with nevirapine (NVP); some episodes began during the first few weeks of therapy (FDA, unpublished data, 2000). EFV has been associated with central nervous system side effects, including dizziness, somnolence, insomnia, and abnormal dreaming. All of the approved antiretroviral agents might have potentially serious drug interactions when used with certain other drugs (Appendix C). Careful evaluation of concomitant medications used by an exposed person is required before PEP is prescribed, and close monitoring for toxicity is also needed. Further information about potential drug interactions can be found in the manufacturer’s package insert.

Toxicity Associated with PEP. Information from the National Surveillance System for Health Care Workers (NaSH) and the HIV Postexposure Registry indicates that nearly 50% of HCP experience adverse symptoms (e.g., nausea, malaise, headache, anorexia, and headache) while taking PEP and that approximately 33% stop taking PEP because of adverse signs and symptoms (6,7,10,11 ). Some studies have demonstrated that side effects and discontinuation of PEP are more common among HCP taking three-drug combination regimens for PEP compared with HCP taking two-drug combination regimens (7,10 ). Although similar rates of side effects were observed among persons who took PEP after sexual or drug use exposures to HIV in the San Francisco Post-Exposure Prevention Project, 80% completed 4 weeks of therapy (149 ). Participants in the San Francisco Project were followed at 1, 2, 4, 26, and 52 weeks postexposure and received medication adherence counseling; most participants took only two drugs for PEP. Serious side effects, including nephrolithiasis, hepatitis, and pancytopenia have been reported with the use of combination drugs for PEP (6,7,150,151 ). One case of NVP- associated fulminant liver failure requiring liver transplantation and one case of hypersensitivity syndrome have been reported in HCP taking NVP for HIV PEP (152 ). Including these two cases, from March 1997 through September 2000, FDA received reports of 22 cases of serious adverse events related to NVP taken for PEP (153 ). These events included 12 cases of hepatotoxicity, 14 cases of skin reaction (including one documented and two possible cases of Stevens-Johnson syndrome), and one case of rhabdomyolysis; four cases involved both hepatotoxicty and skin reaction, and one case involved both rhabdomyolysis and skin reaction.

Resistance to Antiretroviral Agents. Known or suspected resistance of the source virus to antiretroviral agents, particularly to agents that might be included in a PEP regimen, is a concern for persons making decisions about PEP. Resistance to HIV infection occurs with all of the available antiretroviral agents, and cross-resistance within drug classes is frequent (154 ). Recent studies have demonstrated an emergence of drug- resistant HIV among source persons for occupational exposures (143,155 ). A study conducted at seven U.S. sites during 1998–1999 found that 16 (39%) of 41 source persons whose virus was sequenced had primary genetic mutations associated with resistance to RTIs, and 4 (10%) had primary mutations associated with resistance to PIs (143 ). In addition, occupational transmission of resistant HIV strains, despite PEP with combination drug regimens, has been reported (137,139 ). In one case, a hospital worker became infected after an HIV exposure Vol. 50/No. RR-11 MMWR 13 despite a PEP regimen that included ddI, d4T, and NVP (139 ). The transmitted HIV contained two primary genetic mutations associated with resistance to NNRTIs (the source person was taking EFV at the time of the exposure). Despite recent studies and case reports, the relevance of exposure to a resistant virus is still not well understood. Empiric decisions about the presence of antiretroviral drug resistance are often difficult to make because patients generally take more than one antiretroviral agent. Resis- tance should be suspected in source persons when they are experiencing clinical progression of disease or a persistently increasing viral load, and/or decline in CD4 T-cell count, despite therapy or a lack of virologic response to therapy. However, resistance testing of the source virus at the time of an exposure is not practical because the results will not be available in time to influence the choice of the initial PEP regimen. Further- more, in this situation, whether modification of the PEP regimen is necessary or will influence the outcome of an occupational exposure is unknown. No data exist to suggest that modification of a PEP regimen after receiving results from resistance testing (usually a minimum of 1–2 weeks) improves efficacy of PEP.

Antiretroviral Drugs During Pregnancy. Data are limited on the potential effects of antiretroviral drugs on the developing fetus or neonate (156 ). Carcinogenicity and/or mutagenicity is evident in several in vitro screening tests for ZDV and all other FDA- licensed NRTIs. The relevance of animal data to humans is unknown; however, because teratogenic effects were observed in primates at drug exposures similar to those repre- senting human therapeutic exposure, the use of EFV should be avoided in pregnant women (140 ). IDV is associated with infrequent side effects in adults (i.e., hyperbilirubinemia and renal stones) that could be problematic for a newborn. Because the half-life of IDV in adults is short, these concerns might be relevant only if the drug is administered shortly before delivery. In a recent study in France of perinatal HIV transmission, two cases of progressive neurologic disease and death were reported in uninfected infants exposed to ZDV and 3TC (157 ). Laboratory studies of these children suggested mitochondrial dysfunction. In a careful review of deaths in children followed in U.S. perinatal HIV cohorts, no deaths attributable to mitochondrial disease have been found (158 ). Recent reports of fatal and nonfatal lactic acidosis in pregnant women treated throughout gestation with a combination of d4T and ddI have prompted warnings about use of these drugs during pregnancy (159 ). Although the case-patients were HIV-infected women taking the drugs for >4 weeks, pregnant women and their providers should be advised to consider d4T and ddI only when the benefits of their use outweigh the risks. PEP Use in Hospitals in the United States. Analysis of data from NaSH provides information on the use of PEP following occupational exposures in 47 hospitals in the United States. A total of 11,784 exposures to blood and body fluids was reported from June 1996 through November 2000 (CDC, unpublished data, 2001). For all exposures with known sources, 6% were to HIV-positive sources, 74% to HIV-negative sources, and 20% to sources with an unknown HIV status. Sixty-three percent of HCP exposed to a known HIV-positive source started PEP, and 54% of HCP took it for at least 20 days, whereas 14% of HCP exposed to a source person subsequently found to be HIV- negative initiated PEP, and 3% of those took it for at least 20 days. Information recorded about HIV exposures in NaSH indicates that 46% of exposures involving an HIV-positive source warranted only a two-drug PEP regimen (i.e., the exposure was to mucous membranes or skin or was a superficial percutaneous injury and the source person did not have end- stage AIDS or acute HIV illness); however, 53% of these exposed HCP took >3 drugs (CDC, unpublished data, 2000). Similarly, the National Clinicians’ Post-Exposure Prophy- laxis Hotline (PEPline) reported that PEPline staff recommended stopping or not starting PEP for approximately one half of the HCP who consulted them about exposures (D. Bangsberg, San Francisco General Hospital, unpublished data, September 1999). The observation that some HCP exposed to HIV-negative source persons take PEP from several days Vol. 50/No. RR-11 MMWR 14 to weeks following their exposures suggests that strategies be employed such as the use of a rapid HIV antibody assay, which could minimize exposure to unnecessary PEP (11 ). A recent study demonstrated that use of a rapid HIV test for evaluation of source persons after occupational exposures not only resulted in decreased use of PEP, but also was cost-effective compared with use of the standard enzyme immunoassay (EIA) test for source persons subsequently found to be HIV-negative (160 ).

RECOMMENDATIONS FOR THE MANAGEMENT OF HCP POTENTIALLY EXPOSED TO HBV, HCV, or HIV

Exposure prevention remains the primary strategy for reducing occupational bloodborne pathogen infections; however, occupational exposures will continue to occur. Health-care organizations should make available to their personnel a system that includes written protocols for prompt reporting, evaluation, counseling, treatment, and follow-up of occupational exposures that might place HCP at risk for acquiring a bloodborne infection. HCP should be educated concerning the risk for and prevention of bloodborne infections, including the need to be vaccinated against hepatitis B (17,21,161– 163 ). Employers are required to establish exposure-control plans that include postexposure follow-up for their employees and to comply with incident reporting requirements mandated by the 1992 OSHA bloodborne pathogen standard (2 ). Access to clinicians who can provide postexposure care should be available during all working hours, including nights and weekends. HBIG, hepatitis B vaccine, and antiretroviral agents for HIV PEP should be available for timely administration (i.e., either by providing access on-site or by creating linkages with other facilities or providers to make them available off-site). Persons responsible for providing postexposure management should be familiar with evaluation and treatment protocols and the facility’s plans for accessing HBIG, hepatitis B vaccine, and antiretroviral drugs for HIV PEP. HCP should be educated to report occupational exposures immediately after they occur, particularly because HBIG, hepatitis B vaccine, and HIV PEP are most likely to be effective if administered as soon after the exposure as possible. HCP who are at risk for occupational exposure to bloodborne pathogens should be familiarized with the principles of postexposure management as part of job orientation and ongoing job training.

Hepatitis B Vaccination

Any person who performs tasks involving contact with blood, blood-contaminated body fluids, other body fluids, or sharps should be vaccinated against hepatitis B (2,21 ). Prevaccination serologic screening for previous infection is not indicated for persons being vaccinated because of occupational risk, unless the hospital or health-care organization considers screening cost-effective. Hepatitis B vaccine should always be administered by the intramuscular route in the deltoid muscle with a needle 1–1.5 inches long. Hepatitis B vaccine can be administered at the same time as other vaccines with no interference with antibody response to the other vaccines (164 ). If the vaccination series is interrupted after the first dose, the second dose should be administered as soon as possible. The second and third doses should be separated by an interval of at least 2 months. If only the third dose is delayed, it should be administered when convenient. HCP who have contact with patients or blood and are at ongoing risk for percutaneous injuries should be tested 1–2 months after completion of the 3-dose vaccination series for anti-HBs (21 ). Persons who do not respond to the primary vaccine series (i.e., anti-HBs <10 mIU/mL) should complete a second 3-dose vaccine series or be evaluated to determine if they are HBsAg-positive. Revaccinated persons should be retested at the completion of the second vaccine series. Persons who do not respond to an initial 3-dose vaccine series have a 30%–50% chance of responding to a second 3-dose series (165 ). Persons who prove to be HBsAg-positive should be counseled regarding how to prevent HBV transmission to others and Vol. 50/No. RR-11 MMWR 15 regarding the need for medical evaluation (12,163,166 ). Nonresponders to vaccination who are HBsAg-negative should be considered susceptible to HBV infection and should be counseled regarding precautions to prevent HBV infection and the need to obtain HBIG prophylaxis for any known or probable parenteral exposure to HBsAg-positive blood. Booster doses of hepatitis B vaccine are not necessary, and periodic serologic testing to monitor antibody concentrations after completion of the vaccine series is not recommended. Any blood or body fluid exposure sustained by an unvaccinated, susceptible person should lead to the initiation of the hepatitis B vaccine series.

Treatment of an Exposure Site

Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water; mucous membranes should be flushed with water. No evidence exists that using antiseptics for wound care or expressing fluid by squeezing the wound further reduces the risk of bloodborne pathogen transmission; however, the use of antiseptics is not contraindicated. The application of caustic agents (e.g., bleach) or the injection of antiseptics or disinfectants into the wound is not recommended.

Exposure Report

If an occupational exposure occurs, the circumstances and postexposure management should be recorded in the exposed person’s confidential medical record (usually on a form the facility designates for this purpose) (Box 1). In addition, employers should follow all federal (including OSHA) and state requirements for recording and reporting occupational injuries and exposures.

BOX 1. Recommendations for the contents of the occupational exposure report  date and time of exposure;  details of the procedure being performed, including where and how the exposure occurred; if related to a sharp device, the type and brand of device and how and when in the course of handling the device the exposure occurred;  details of the exposure, including the type and amount of fluid or material and the severity of the exposure (e.g., for a percutaneous exposure, depth of injury and whether fluid was injected; for a skin or mucous membrane exposure, the estimated volume of material and the condition of the skin [e.g., chapped, abraded, intact]);  details about the exposure source (e.g., whether the source material contained HBV, HCV, or HIV; if the source is HIV-infected, the stage of disease, history of antiretroviral therapy, viral load, and antiretroviral resistance information, if known);  details about the exposed person (e.g., hepatitis B vaccination and vaccine-response status); and  details about counseling, postexposure management, and follow-up.

Evaluation of the Exposure and the Exposure Source

Evaluation of the Exposure

The exposure should be evaluated for the potential to transmit HBV, HCV, and HIV based on the type of body substance involved and the route and severity of the exposure (Box 2). Blood, fluid containing visible blood, or other potentially infectious fluid (including semen; vaginal secretions; and cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids) or tissue can be infectious for bloodborne viruses. Exposures to these fluids or tissue through a percutaneous injury Vol. 50/No. RR-11 MMWR 16 (i.e., needlestick or other penetrating sharps-related event) or through contact with a mucous membrane are situations that pose a risk for bloodborne virus transmission and require further evaluation. For HCV and HIV, exposure to a blood-filled hollow needle or visibly bloody device suggests a higher risk exposure than exposure to a needle that was most likely used for giving an injection. In addition, any direct contact (i.e, personal protective equipment either was not present or was ineffective in protecting skin or mucous membranes) with concentrated virus in a research laboratory or production facility is considered an exposure that requires clinical evaluation. For skin exposure, follow-up is indicated only if it involves exposure to a body fluid previously listed and evidence exists of compromised skin integrity (e.g., dermatitis, abrasion, or open wound). In the clinical evaluation for human bites, possible exposure of both the person bitten and the person who inflicted the bite must be considered. If a bite results in blood exposure to either person involved, postexposure follow-up should be provided.

BOX 2. Factors to consider in assessing the need for follow-up of occupational exposures  Type of exposure --Percutaneous injury --Mucous membrane exposure --Nonintact skin exposure --Bites resulting in blood exposure to either person involved  Type and amount of fluid/tissue --Blood --Fluids containing blood --Potentially infectious fluid or tissue (semen; vaginal secretions; and cerebrospinal, synovial, -----pleural, peritoneal, pericardial, and amniotic fluids) --Direct contact with concentrated virus  Infectious status of source --Presence of HBsAg --Presence of HCV antibody --Presence of HIV antibody  Susceptibility of exposed person --Hepatitis B vaccine and vaccine response status --HBV, HCV, and HIV immune status

Evaluation of the Exposure Source

The person whose blood or body fluid is the source of an occupational exposure should be evaluated for HBV, HCV, and HIV infection (Box 3). Information available in the medical record at the time of exposure (e.g., laboratory test results, admitting diagnosis, or previous medical history) or from the source person, might confirm or exclude bloodborne virus infection. If the HBV, HCV, and/or HIV infection status of the source is unknown, the source person should be informed of the incident and tested for serologic evidence of bloodborne virus infection. Procedures should be followed for testing source persons, including obtaining informed consent, in accordance with applicable state and local laws. Any persons determined to be infected with HBV, HCV, or HIV should be referred for appropriate counseling and treatment. Confidentiality of the source person should be maintained at all times. Testing to determine the HBV, HCV, and HIV infection status of an exposure source should be performed as soon as possible. Hospitals, clinics and other sites that manage exposed HCP should consult their laboratories regarding the most appropriate test to use to expedite obtaining these results. An FDA-approved rapid HIV-antibody test kit should be considered for use in this situation, particularly Vol. 50/No. RR-11 MMWR 17 if testing by EIA cannot be completed within 24–48 hours. Repeatedly reactive results by EIA or rapid HIV-antibody tests are considered to be highly suggestive of infection, whereas a negative result is an excellent indicator of the absence of HIV antibody. Confirmation of a reactive result by Western blot or immunofluorescent antibody is not necessary to make initial decisions about postexposure management but should be done to complete the testing process and before informing the source person. Repeatedly reactive results by EIA for anti-HCV should be confirmed by a supplemental test (i.e., recombinant immunoblot assay [RIBA™] or HCV PCR). Direct virus assays (e.g., HIV p24 antigen EIA or tests for HIV RNA or HCV RNA) for routine HIV or HCV screening of source persons are not recommended. If the exposure source is unknown or cannot be tested, information about where and under what circumstances the exposure occurred should be assessed epidemiologically for the likelihood of transmission of HBV, HCV, or HIV. Certain situations as well as the type of exposure might suggest an increased or decreased risk; an important consideration is the prevalence of HBV, HCV, or HIV in the population group (i.e., institution or community) from which the contaminated source material is derived. For example, an exposure that occurs in a geographic area where injection-drug use is prevalent or involves a needle discarded in a drug-treatment facility would be considered epidemiologically to have a higher risk for transmission than an exposure that occurs in a nursing home for the elderly. Testing of needles or other sharp instruments implicated in an exposure, regardless of whether the source is known or unknown, is not recommended. The reliability and interpretation of findings in such circumstances are unknown, and testing might be haz- ardous to persons handling the sharp instrument. Examples of information to consider when evaluating an exposure source for possible HBV, HCV, or HIV infection include laboratory information (e.g., previous HBV, HCV, or HIV test results or results of immunologic testing [e.g., CD4+ T-cell count]) or liver enzymes (e.g., ALT), clinical symptoms (e.g., acute syndrome suggestive of primary HIV infection or undiagnosed immunodeficiency disease), and history of recent (i.e., within 3 months) possible HBV, HCV, or HIV exposures (e.g., injection-drug use or sexual contact with a known positive partner). Health-care providers should be aware of local and state laws governing the collection and release of HIV serostatus information on a source person, following an occupational exposure. If the source person is known to have HIV infection, available information about this person’s stage of infection (i.e., asymptomatic, symptomatic, or AIDS), CD4+ T-cell count, results of viral load testing, current and previous antiretroviral therapy, and results of any genotypic or phenotypic viral resistance testing should be gathered for consideration in choosing an appropriate PEP regimen. If this information is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate. Reevaluation of exposed HCP should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. If the source person is HIV seronegative and has no clinical evidence of AIDS or symptoms of HIV infection, no further testing of the person for HIV infection is indicated. The likelihood of the source person being in the “window period” of HIV infection in the absence of symptoms of acute retroviral syndrome is extremely small. Vol. 50/No. RR-11 MMWR 18

BOX 3. Evaluation of occupational exposure sources Known sources  Test known sources for HBsAg, anti-HCV, and HIV antibody --Direct virus assays for routine screening of source patients are not recommended --Consider using a rapid HIV-antibody test --If the source person is not infected with a bloodborne pathogen, baseline testing or further follow-up of the exposed person is not necessary  For sources whose infection status remains unknown (e.g., the source person refuses testing), consider medical diagnoses, clinical symptoms, and history of risk behaviors  Do not test discarded needles for bloodborne pathogens Unknown sources • For unknown sources, evaluate the likelihood of exposure to a source at high risk for infection --Consider likelihood of bloodborne pathogen infection among patients in the exposure setting

Management of Exposures to HBV

For percutaneous or mucosal exposures to blood, several factors must be considered when making a decision to provide prophylaxis, including the HBsAg status of the source and the hepatitis B vaccination and vaccine-response status of the exposed person. Such exposures usually involve persons for whom hepatitis B vaccination is recommended. Any blood or body fluid exposure to an unvaccinated person should lead to initiation of the hepatitis B vaccine series. The hepatitis B vaccination status and the vaccine-response status (if known) of the exposed person should be reviewed. A summary of prophylaxis recommendations for percutaneous or mucosal exposure to blood according to the HBsAg status of the exposure source and the vaccination and vaccine-response status of the exposed person is included in this report (Table 3). When HBIG is indicated, it should be administered as soon as possible after exposure (preferably within 24 hours). The effectiveness of HBIG when administered >7 days after exposure is unknown. When hepatitis B vaccine is indicated, it should also be administered as soon as possible (preferably within 24 hours) and can be administered simultaneously with HBIG at a separate site (vaccine should always be administered in the deltoid muscle). For exposed persons who are in the process of being vaccinated but have not completed the vaccination series, vaccination should be completed as scheduled, and HBIG should be added as indicated (Table 3). Persons exposed to HBsAg-positive blood or body fluids who are known not to have responded to a primary vaccine series should receive a single dose of HBIG and reinitiate the hepatitis B vaccine series with the first dose of the hepatitis B vaccine as soon as possible after exposure. Alternatively, they should receive two doses of HBIG, one dose as soon as possible after exposure, and the second dose 1 month later. The option of administering one dose of HBIG and reinitiating the vaccine series is preferred for nonresponders who did not complete a second 3-dose vaccine series. For persons who previously completed a second vaccine series but failed to respond, two doses of HBIG are preferred.

Management of Exposures to HCV

Individual institutions should establish policies and procedures for testing HCP for HCV after percutaneous or mucosal exposures to blood and ensure that all personnel are familiar with these policies and procedures. The following are recommendations for follow-up of occupational HCV exposures:  For the source, perform testing for anti-HCV  For the person exposed to an HCV-positive source --perform baseline testing for anti-HCV and ALT activity; and --perform follow-up testing (e.g., at 4–6 months) for anti-HCV and ALT activity (if earlier diagnosis of HCV infection is desired, testing for HCV RNA may be performed at 4–6 weeks). Vol. 50/No. RR-11 MMWR 19

 Confirm all anti-HCV results reported positive by enzyme immunoassay using supplemental anti-HCV testing (e.g., recombinant immunoblot assay [RIBA™]) (13 ). Health-care professionals who provide care to persons exposed to HCV in the occupational setting should be knowledgeable regarding the risk for HCV infection and appropriate counseling, testing, and medical follow-up. IG and antiviral agents are not recommended for PEP after exposure to HCV-positive blood. In addition, no guidelines exist for administration of therapy during the acute phase of HCV infection. However, limited data indicate that antiviral therapy might be beneficial when started early in the course of HCV infection. When HCV infection is identified early, the person should be referred for medical management to a specialist knowledgeable in this area.

Counseling for HCP Exposed to Viral Hepatitis

HCP exposed to HBV- or HCV-infected blood do not need to take any special precautions to prevent secondary transmission during the follow-up period (12,13 ); however, they should refrain from donating blood, plasma, organs, tissue, or semen. The exposed person does not need to modify sexual practices or refrain from becoming pregnant. If an exposed woman is breast feeding, she does not need to discontinue. No modifications to an exposed person’s patient-care responsibilities are necessary to prevent transmission to patients based solely on exposure to HBV- or HCV-positive blood. If an exposed person becomes acutely infected with HBV, the person should be evaluated according to published recommendations for infected HCP (165 ). No recommendations exist regarding restricting the professional activities of HCP with HCV infection (13 ). As recommended for all HCP, those who are chronically infected with HBV or HCV should follow all recommended infection-control practices, including standard precautions and appropriate use of hand washing, protective barriers, and care in the use and disposal of needles and other sharp instruments (162 ).

Management of Exposures to HIV

Clinical Evaluation and Baseline Testing of Exposed HCP

HCP exposed to HIV should be evaluated within hours (rather than days) after their exposure and should be tested for HIV at baseline (i.e., to establish infection status at the time of exposure). If the source person is seronegative for HIV, baseline testing or further follow-up of the exposed person normally is not necessary. Serologic testing should be made available to all HCP who are concerned that they might have been occupationally infected with HIV. For purposes of considering HIV PEP, the evaluation also should include information about medications the exposed person might be taking and any current or underlying medical conditions or circumstances (i.e., pregnancy, breast feeding, or renal or hepatic disease) that might influence drug selection.

PEP for HIV

The following recommendations (Tables 4 and 5) apply to situations when a person has been exposed to a source person with HIV infection or when information suggests the likelihood that the source person is HIV-infected. These recommendations are based on the risk for HIV infection after different types of exposure and on limited data regarding efficacy and toxicity of PEP. Because most occupational HIV exposures do not result in the transmission of HIV, potential toxicity must be carefully considered when prescribing PEP. To assist with the initial management of an HIV exposure, health- care facilities should have drugs for an initial PEP regimen selected and available for use. When Vol. 50/No. RR-11 MMWR 20 possible, these recommendations should be implemented in consultation with persons who have expertise in antiretroviral therapy and HIV transmission (Box 4).

TABLE 2. Primary side effects associated with antiretroviral agents Antiretroviral class/agent Primary side effects and toxicities Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine (Retrovir™; ZDV; AZT) anemia, neutropenia, nausea, headache, insomnia, muscle pain, and weakness Lamivudine (Epivir™; 3TC) abdominal pain, nausea, diarrhea, rash, and pancreatitis Stavudine (Zerit™; d4T) peripheral neuropathy, headache, diarrhea, nausea, insomnia, anorexia, pancreatitis, increased liver function tests (LFTs), anemia, and neutropenia Didanosine (Videx™; ddI) pancreatitis, lactic acidosis, neuropathy, diarrhea, abdominal pain, and nausea Abacavir (Ziagen™; ABC) nausea, diarrhea, anorexia, abdominal pain, fatigue, headache, insomnia, and hypersensitivity reactions Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine (Viramune™; NVP) rash (including cases of Stevens-Johnson syndrome), fever, nausea, headache, hepatitis, and increased LFTs Delavirdine (Rescriptor™; DLV) rash (including cases of Stevens-Johnson syndrome), nausea, diarrhea, headache, fatigue, and increased LFTs Efavirenz (Sustiva™; EFV) rash (including cases of Stevens-Johnson syndrome), insomnia, somnolence, dizziness, trouble concentrating, and abnormal dreaming Protease inhibitors (PIs) Indinavir (Crixivan™; IDV) nausea, abdominal pain, nephrolithiasis, and indirect hyperbilirubinemia Nelfinavir (Viracept™; NFV) diarrhea, nausea, abdominal pain, weakness, and rash Ritonavir (Norvir™; RTV) weakness, diarrhea, nausea, circumoral paresthesia, taste alteration, and increased cholesterol and triglycerides Saquinavir (Fortovase™; SQV) diarrhea, abdominal pain, nausea, hyperglycemia, and increased LFTs Amprenavir (Agenerase™; AMP) nausea, diarrhea, rash, circumoral paresthesia, taste alteration, and depression Lopinavir/Ritonavir (Kaletra™) diarrhea, fatigue, headache, nausea, and increased cholesterol and triglycerides Vol. 50/No. RR-11 MMWR 21

TABLE 3. Recommended postexposure prophylaxis for exposure to hepatitis B virus Vaccination and Treatment antibody response Source Source Source status of exposed HBsAg† positive HBsAg† negative unknown or not workers* available for testing Unvaccinated HBIG§ x 1 and initiate Initiate HB vaccine Initiate HB vaccine HB vaccine series¶ series series Previously vaccinated Known responder** No treatment No treatment No treatment Known nonresponder†† HBIG x 1 and initiate No treatment If known high risk source, revaccination treat as if source were or HBIG x 2§§ HBsAg positive Antibody response Test exposed no treatment Test exposed person for unknown person. No treatment for anti-HBs anti-HBs¶¶ 1. If adequate,¶ no 1. If adequate,** no treatment is treatment is necessary,†† necessary 2. If inadequate,¶ 2. If inadequate administer vaccine administer HBIG x 1 booster recheck titer in and vaccine booster 1–2 months *

*Persons who have previously been infected with HBV are immune to reinfection and do not require postexposure prophylaxis.

†Hepatitis B surface antigen.

§Hepatitis B immune globulin; dose is 0.06 mL/kg intramuscularly.

¶Hepatitis B vaccine.

** A responder is a person with adequate levels of serum antibody to HBsAg (i.e., anti-HBs >10 mIU/mL).

††A nonresponder is a person with inadequate response to vaccination (i.e., serum anti-HBs < 10 mIU/mL).

§§The option of giving one dose of HBIG and reinitiating the vaccine series is preferred for nonresponders who have not completed a second 3-dose vaccine series. For persons who previously completed a second vaccine series but failed to respond, two doses of HBIG are preferred.

¶¶ Antibody to HBsAg. Vol. 50/No. RR-11 MMWR 22 TABLE 4. Recommended HIV postexposure prophylaxis for percutaneous injuries

Infection status of source Source of Exposure HIV-Positive HIV-Positive HIV- unknown HIV Unknown source§ type Class 1* Class 2* Negative status† Generally, no PEP Generally, no PEP warranted; however, warranted; consider basic for 2- Recommend however, consider No PEP Less Recommend drug PEP** in expanded 3- basic 2-drug warranted severe¶ 2-drug PEP settings where drug PEP PEP** for source exposure to HIV- with HIV risk infected persons is factors†† likely Generally, no PEP Generally, no PEP warranted; however, warranted; consider basic for 2- Recommend Recommend More however, consider drug PEP** in No PEP expanded3- expanded 3- severe§§ basic 2-drug PEP** settings where warranted drug PEP drug PEP for source with HIV exposure to HIV- risk factors†† infectedpersons is likely *

* HIV-Positive, Class 1 — asymptomatic HIV infection or known low viral load (e.g., <1,500 RNA copies/mL). HIV-Positive, Class 2 — symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load. If drug resistance is a concern, obtain expert consultation. Initiation of postexposure prophylaxis (PEP) should not be delayed pending expert consultation, and, because expert consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures.

†Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing).

§Unknown source (e.g., a needle from a sharps disposal container).

¶Less severe (e.g., solid needle and superficial injury).

** The designation “consider PEP” indicates that PEP is optional and should be based on an individualized decision between the exposed person and the treating clinician.

††If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued.

§§More severe (e.g., large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient’s artery or vein). †† Vol. 50/No. RR-11 MMWR 23

TABLE 5. Recommended HIV postexposure prophylaxis for mucous membrane exposures and nonintact skin* exposures

Infection status of source HIV- HIV- Source of Exposure Unknown Positive Positive unknown HIV HIV-Negative type source¶ Class 1† Class 2† status§ Generally, no Generally, no PEP warranted; PEP warranted; however, Consider Recommend however, consider basic 2- Small basic 2-drug basic 2-drug consider basic 2- drug PEP†† in No PEP warranted volume** PEP†† PEP drug PEP†† for settings where with HIV risk exposure to factors§§ HIV- infected persons is likely Generally, no Generally, no PEP warranted; PEP warranted; however, Recommend Recommend however, consider basic 2- Large basic 2-drug expanded 3- consider basic 2- drug PEP†† in No PEP warranted volume¶¶ PEP drug PEP drug PEP†† for settings where source with HIV exposure to risk factors§§ HIV-infected persons is likely

* For skin exposures, follow-up is indicated only if there is evidence of compromised skin integrity (e.g., dermatitis, abrasion, or open wound).

†HIV-Positive, Class 1 — asymptomatic HIV infection or known low viral load (e.g., <1,500 RNA copies/mL). HIV-Positive, Class 2 — symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load. If drug resistance is a concern, obtain expert consultation. Initiation of postexposure prophylaxis (PEP) should not be delayed pending expert consultation, and, because expert consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures.

§Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing). ¶Unknown source (e.g., splash from inappropriately disposed blood).

** Small volume (i.e., a few drops).

††The designation, “consider PEP,” indicates that PEP is optional and should be based on an individualized decision between the exposed person and the treating clinician.

§§If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued.

¶¶Large volume (i.e., major blood splash). Vol. 50/No. RR-11 MMWR 24 Timing and Duration of PEP. PEP should be initiated as soon as possible. The interval within which PEP should be initiated for optimal efficacy is not known. Animal studies have demonstrated the importance of starting PEP soon after an exposure (111,112,118 ). If questions exist about which antiretroviral drugs to use or whether to use a basic or expanded regimen, starting the basic regimen immediately rather than delaying PEP administration is probably better. Although animal studies suggest that PEP probably is substantially less effective when started more than 24–36 hours postexposure (112,119,122 ), the interval after which no benefit is gained from PEP for humans is undefined. Therefore, if appropriate for the exposure, PEP should be started even when the interval since exposure exceeds 36 hours. Initiating therapy after a longer interval (e.g., 1 week) might be considered for exposures that represent an increased risk for transmission. The optimal duration of PEP is unknown. Because 4 weeks of ZDV ap- peared protective in occupational and animal studies (100,123 ), PEP probably should be administered for 4 weeks, if tolerated. Use of PEP When HIV Infection Status of Source Person is Unknown. If the source person’s HIV infection status is unknown at the time of exposure, use of PEP should be decided on a case-by-case basis, after considering the type of exposure and the clinical and/or epidemiologic likelihood of HIV infection in the source (Tables 4 and 5). If these considerations suggest a possibility for HIV transmission and HIV testing of the source person is pending, initiating a two-drug PEP regimen until laboratory results have been obtained and later modifying or discontinuing the regimen accordingly is reasonable. The following are recommendations regarding HIV postexposure prophylaxis:  If indicated, start PEP as soon as possible after an exposure.  Reevaluation of the exposed person should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available. • Administer PEP for 4 weeks, if tolerated.  If a source person is determined to be HIV-negative, PEP should be discontinued.

PEP for Pregnant HCP. If the exposed person is pregnant, the evaluation of risk of infection and need for PEP should be approached as with any other person who has had an HIV exposure. However, the decision to use any antiretroviral drug during pregnancy should involve discussion between the woman and her health-care provider(s) regarding the potential benefits and risks to her and her fetus. Certain drugs should be avoided in pregnant women. Because teratogenic effects were observed in primate studies, EFV is not recommended during pregnancy. Reports of fatal lactic acidosis in pregnant women treated with a combination of d4T and ddI have prompted warnings about these drugs during pregnancy. Because of the risk of hyperbilirubinemia in newborns, IDV should not be administered to pregnant women shortly before delivery.

Recommendations for the Selection of Drugs for HIV PEP

Health-care providers must strive to balance the risk for infection against the potential toxicity of the agent(s) used when selecting a drug regimen for HIV PEP. Because PEP is potentially toxic, its use is not justified for exposures that pose a negligible risk for transmission (Tables 4 and 5). Also, insufficient evidence exists to support recommend- ing a three-drug regimen for all HIV exposures. Therefore, two regimens for PEP are provided (Appendix C): a “basic” two-drug regimen that should be appropriate for most HIV exposures and an “expanded” three-drug regimen that should be used for exposures that pose an increased risk for transmission (Tables 4 and 5). When possible, the regimens should be implemented in consultation with persons who have expertise in antiretroviral treatment and HIV transmission. Most HIV exposures will warrant a two-drug regimen using two nucleoside analogues (e.g., ZDV and 3TC; or 3TC and d4T; or d4T and ddI). The addition of a third drug should be considered for exposures that pose an increased risk for transmission. Selec- tion of the PEP regimen should consider the comparative risk represented by the exposure and information about the exposure source, Vol. 50/No. RR-11 MMWR 25 including history of and response to antiretroviral therapy based on clinical response, CD4+ T-cell counts, viral load measure- ments, and current disease stage. When the source person’s virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person’s virus is unlikely to be resistant is recommended; expert consultation is advised. If this information is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate. Reevaluation of the exposed person should be considered within 72 hours postexposure, especially as additional information about the exposure or source person becomes available.

Follow-up of HCP Exposed to HIV

Postexposure Testing. HCP with occupational exposure to HIV should receive follow- up counseling, postexposure testing, and medical evaluation, regardless of whether they receive PEP. HIV-antibody testing should be performed for at least 6 months postexposure (e.g., at 6 weeks, 12 weeks, and 6 months). Extended HIV follow-up (e.g., for 12 months) is recommended for HCP who become infected with HCV following exposure to a source coinfected with HIV and HCV. Whether extended follow-up is indicated in other circumstances (e.g., exposure to a source coinfected with HIV and HCV in the absence of HCV seroconversion or for exposed persons with a medical history suggesting an impaired ability to develop an antibody response to acute infection) is unclear. Although rare instances of delayed HIV seroconversion have been reported (167,168 ), the infrequency of this occurrence does not warrant adding to the anxiety level of the exposed persons by routinely extending the duration of postexposure follow-up. However, this recommendation should not preclude a decision to extend follow-up in an individual situation based on the clinical judgement of the exposed person’s health-care provider. HIV testing should be performed on any exposed person who has an illness that is compatible with an acute retroviral syndrome, regardless of the interval since exposure. When HIV infection is identified, the person should be referred to a specialist knowledgeable in the area of HIV treatment and counseling for medical management. HIV-antibody testing with EIA should be used to monitor for seroconversion. The routine use of direct virus assays (e.g., HIV p24 antigen EIA or tests for HIV RNA) to detect infection in exposed HCP generally is not recommended (169 ). The high rate of false- positive results of these tests in this setting could lead to unnecessary anxiety and/or treatment (170,171 ). Despite the ability of direct virus assays to detect HIV infection a few days earlier than EIA, the infrequency of occupational seroconversion and increased costs of these tests do not warrant their routine use in this setting.  HIV-antibody testing should be performed for at least 6 months postexposure.  Direct virus assays for routine follow-up of HCP are not recommended.  HIV testing should be performed on any exposed person who has an illness compatible with an acute retroviral syndrome.

Monitoring and Management of PEP Toxicity. If PEP is used, HCP should be monitored for drug toxicity by testing at baseline and again 2 weeks after starting PEP. The scope of testing should be based on medical conditions in the exposed person and the toxicity of drugs included in the PEP regimen. Minimally, lab monitoring for toxicity should include a complete blood count and renal and hepatic function tests. Monitoring for evidence of hyperglycemia should be included for HCP whose regimens include any PI; if the exposed person is receiving IDV, monitoring for crystalluria, hematuria, hemolytic anemia, and hepatitis also should be included. If toxicity is noted, modification of the regimen should be considered after expert consultation; further diagnostic studies may be indicated. Exposed HCP who choose to take PEP should be advised of the importance of completing the prescribed regimen. Information should be provided to HCP about potential drug interactions and the drugs that should not be taken with PEP, the side effects of the drugs that have been prescribed, measures to minimize these effects, and the methods of clinical monitoring for toxicity during the follow- Vol. 50/No. RR-11 MMWR 26 up period. HCP should be advised that the evaluation of certain symptoms should not be delayed (e.g., rash, fever, back or abdominal pain, pain on urination or blood in the urine, or symptoms of hyperglycemia [increased thirst and/or frequent urination]). HCP who fail to complete the recommended regimen often do so because of the side effects they experience (e.g., nausea and diarrhea). These symptoms often can be managed with antimotility and antiemetic agents or other medications that target the specific symptoms without changing the regimen. In other situations, modifying the dose interval (i.e., administering a lower dose of drug more frequently throughout the day, as recommended by the manufacturer), might facilitate adherence to the regimen. Serious adverse events should be reported to FDA’s MedWatch Program.

Counseling and Education. Although HIV infection following an occupational exposure occurs infrequently, the emotional effect of an exposure often is substantial (172– 174 ). In addition, HCP are given seemingly conflicting information. Although HCP are told that a low risk exists for HIV transmission, a 4-week regimen of PEP might be recommended, and they are asked to commit to behavioral measures (e.g., sexual abstinence or condom use) to prevent secondary transmission, all of which influence their lives for several weeks to months (172 ). Therefore, access to persons who are knowledgeable about occupational HIV transmission and who can deal with the many concerns an HIV exposure might generate for the exposed person is an important element of postexposure management. HIV-exposed HCP should be advised to use the following measures to prevent secondary transmission during the follow-up period, especially the first 6–12 weeks after the exposure when most HIV-infected persons are expected to seroconvert: exercise sexual abstinence or use condoms to prevent sexual transmission and to avoid pregnancy; and refrain from donating blood, plasma, organs, tissue, or semen. If an exposed woman is breast feeding, she should be counseled about the risk of HIV transmission through breast milk, and discontinuation of breast feeding should be considered, especially for high-risk exposures. Additionally, NRTIs are known to pass into breast milk, as is NVP; whether this also is true for the other approved antiretroviral drugs is unknown. The patient-care responsibilities of an exposed person do not need to be modified, based solely on an HIV exposure, to prevent transmission to patients. If HIV seroconversion is detected, the person should be evaluated according to published recommendations for infected HCP (175 ). Exposed HCP should be advised to seek medical evaluation for any acute illness that occurs during the follow-up period. Such an illness, particularly if characterized by fever, rash, myalgia, fatigue, malaise, or lymphadenopathy, might be indicative of acute HIV infection but also might be indicative of a drug reaction or another medical condition. For exposures for which PEP is considered appropriate, HCP should be informed that a) knowledge about the efficacy of drugs used for PEP is limited; b) experts recommend combination drug regimens because of increased potency and concerns about drug- resistant virus; c) data regarding toxicity of antiretroviral drugs in persons without HIV infection or in pregnant women are limited; d) although the short-term toxicity of antiretroviral drugs is usually limited, serious adverse events have occurred in persons taking PEP; and e) any or all drugs for PEP may be declined or stopped by the exposed person. HCP who experience HIV occupational exposures for which PEP is not recommended should be informed that the potential side effects and toxicity of taking PEP outweigh the negligible risk of transmission posed by the type of exposure.

Guidelines for counseling and educating HCP with HIV exposure include  Exposed HCP should be advised to use precautions to prevent secondary transmission during the follow-up period.  For exposures for which PEP is prescribed, HCP should be informed about possible drug toxicities and the need for monitoring, and possible drug interactions. Vol. 50/No. RR-11 MMWR 27 Occupational Exposure Management Resources

Several resources are available that provide guidance to HCP regarding the management of occupational exposures. These resources include PEPline; the Needlestick! website; the Hepatitis Hotline; CDC (receives reports of occupationally acquired HIV infections and failures of PEP); the HIV Antiretroviral Pregnancy Registry; FDA (receives reports of unusual or severe toxicity to antiretroviral agents); and the HIV/AIDS Treat- ment Information Service (Box 5).

BOX 4. Situations for which expert* consultation for HIV postexposure prophylaxis is advised  Delayed (i.e., later than 24–36 hours) exposure report --the interval after which there is no benefit from postexposure prophylaxis (PEP) is undefined  Unknown source (e.g., needle in sharps disposal container or laundry) --decide use of PEP on a case-by-case basis --consider the severity of the exposure and the epidemiologic likelihood of HIV exposure --do not test needles or other sharp instruments for HIV  Known or suspected pregnancy in the exposed person --does not preclude the use of optimal PEP regimens --do not deny PEP solely on the basis of pregnancy  Resistance of the source virus to antiretroviral agents --influence of drug resistance on transmission risk is unknown --selection of drugs to which the source person’s virus is unlikely to be resistant is recommended, if the source person’s virus is known or suspected to be resistant to >1 of the drugs considered for the PEP regimen --resistance testing of the source person’s virus at the time of the exposure is not recommended  Toxicity of the initial PEP regimen --adverse symptoms, such as nausea and diarrhea are common with PEP --symptoms often can be managed without changing the PEP regimen by prescribing antimotility and/or antiemetic agents --modification of dose intervals (i.e., administering a lower dose of drug more frequently throughout the day, as recommended by the manufacturer), in other situations, might help alleviate symptoms

*Local experts and/or the National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline [1-888-448- 4911]). Vol. 50/No. RR-11 MMWR 28

BOX 5. Occupational exposure management resources National Clinicians’ Postexposure Phone: (888) 448-4911 Prophylaxis Hotline (PEPline) Internet: http://www.ucsf.edu/hivcntr Run by University of California– San Francisco/San Francisco General Hospital staff; supported by the Health Resources and Services Administration Ryan White CARE Act, HIV/AIDS Bureau, AIDS Education and Training Centers, and CDC.

Needlestick Internet: http://www.needlestick.mednet.ucla.edu A website to help clinicians manage and document occupational blood and body fluid exposures. Developed and maintained by the University of California, Los Angeles (UCLA), Emergency Medicine Center, UCLA School of Medicine, and funded in party by CDC and the Agency for Healthcare Research and Quality.!

Hepatitis Hotline Phone: (888) 443-7232 Internet: http://www.cdc.gov/hepatitis

Reporting to CDC: Occupationally acquired Phone: (800) 893-0485 HIV infections and failures of PEP

HIV Antiretroviral Pregnancy Registry Phone:(800) 258-4263 Fax: (800) 800-1052 Address: 1410 Commonwealth Drive Suite 215 Wilmington, NC 28405 Internet: http://www.glaxowellcome.com/preg_reg/antiretroviral

Food and Drug Administration Phone: (800) 332-1088 Report unusual or severe toxicity to Address: antiretroviral agents MedWatch HF-2, FDA 5600 Fishers Lane Rockville, MD 20857 Internet: http://www.fda.gov/medwatch

HIV/AIDS Treatment Information Service Internet: http://www.hivatis.org Vol. 50/No. RR-11 MMWR 29 References

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139. Beltrami EM, Luo C-C, Dela Torre N, Cardo DM. HIV transmission after an occupational exposure despite postexposure prophylaxis with a combination drug regimen [Abstract P-S2- 62]. In: Program and abstracts of the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections in conjunction with the 10th Annual Meeting of SHEA. Atlanta, GA: CDC, 2000:125–6. 140. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at . Accessed May 9, 2001. 141. Manion DJ, Hirsch MS. Combination chemotherapy for human immunodeficiency virus- 1. Am J Med 1997;102(suppl 5B):76–80. 142. Lafeuillade A, Poggi C, Tamalet C, Profizi N, Tourres C, Costes O. Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis 1997;175:1051–5. 143. Beltrami EM, Cheingsong R, Respess R, Cardo DM. Antiretroviral drug resistance in HIV- infected source patients for occupational exposures to healthcare workers [Abstract P- S2-70]. In: Program and Abstracts of the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections. Atlanta, GA: CDC, 2000:128. 144. Struble KA, Pratt RD, Gitterman SR. Toxicity of antiretroviral agents. Am J Med 1997;102(suppl 5B):65–7. 145. Food and Drug Administration. Protease inhibitors may increase blood glucose in HIV patients. FDA Medical Bulletin 1997;27(2). 146. Dever LL, Oruwari PA, O’Donovan CA, Eng RHK. Hyperglycemia associated with protease inhibitors in HIV-infected patients [Abstract LB-4]. In: Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Ontario, Canada: American Society for Microbiology, 1997. 147. Dubé MP, Johnson DL, Currier JS, Leedom JM. Protease inhibitor-associated hyperglycaemia [Letter]. Lancet 1997;350:713–4. 148. Abramowicz M, ed. New drugs for HIV infection. The Medical Letter on Drugs and Therapeutics 1996;38:35–7. 149. Martin JN, Roland ME, Bamberger JD, et al. Postexposure prophylaxis after sexual or drug use exposure to HIV: final results from the San Francisco Post-Exposure Prevention (PEP) Project [Abstract 196]. In: Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA: Foundation for Retrovirology and Human Health in scientific collaboration with the National Institute of Allergy and Infectious Diseases and CDC, 2000:112. 150. Steger KA, Swotinsky R, Snyder S, Craven DE. Recent experience with post-exposure prophylaxis (PEP) with combination antiretrovirals for occupational exposure (OE) to HIV [Abstract 480]. In: Program and abstracts of the 35th annual meeting of the Infectious Diseases Society of America. Alexandria, VA: Infectious Diseases Society of America, 1997:161. 151. Henry K, Acosta EP, Jochimsen E. Hepatotoxicity and rash associated with zidovudine and zalcitabine chemoprophylaxis [Letter]. Ann Intern Med 1996;124:855. 152. Johnson S, Baraboutis JG; Sha BE, Proia LA, Kessler HA. Adverse effects associated with use of nevirapine in HIV postexposure prophylaxis for 2 health care workers [Letters]. JAMA 2000;284:2722–3. 153. CDC. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures—worldwide, 1997–2000. MMWR 2001;49:1153–6. 154. Hirsch MS, Brun-Vézinet F, D’Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV- 1 infection: recommendations of an international AIDS Society—USA panel. JAMA 2000;283:2417–26 Vol. 50/No. RR-11 MMWR 37

155. Tack PC, Bremer JW, Harris AA, Landay AL, Kessler HA. Genotypic analysis of HIV-1 isolates to identify antiretroviral resistance mutations from source patients involved in health care worker occupational exposures [Letter]. JAMA 1999;281:1085–6. 156. CDC. Public Health Service task force recommendations for use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV- 1 transmission in the United States. MMWR 1998;47(RR-2). 157. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;354:1084–9. 158. Smith ME, US Nucleoside Safety Review Working Group. Ongoing nucleoside safety review of HIV exposed children in US studies [Abstract 96]. In: Final program and abstracts for the Second Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants. Montreal, Canada: New York Academy of Sciences, 1999:49. 159. Food and Drug Administration. Important drug warning. Available at . Accessed May 9, 2001. 160. Veeder AV, McErlean M, Putnam K, Caldwell WC, Venezia RA. The impact of a rapid HIV test to limit unnecessary post exposure prophylaxis following occupational exposures [Abstract P-S2-66]. In: Program and Abstracts of the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections in conjunction with the 10th Annual Meeting of SHEA. Atlanta, GA: CDC, 2000:127. 161. CDC. Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and public-safety workers. MMWR 1989;38(No. S-6). 162. Garner JS, Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17:54–80. 163. CDC. Recommendations for preventing transmission of human immunodeficiency virus and hepatitis B virus to patients during exposure-prone invasive procedures. MMWR 1991;40(No. RR-8). 164. Coursaget P, Yvonnet B, Relyveld EH, Barres JL, Diop-Mar I, Chiron JP. Simultaneous administration of diphtheria-tetanus-pertussis-polio and hepatitis B vaccines in a simplified immunization program: immune response to diphtheria toxoid, tetanus toxoid, pertussis, and hepatitis B surface antigen. Infect Immun 1986;51:784–7. 165. Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med 1986;315:209–14. 166. CDC. Public Health Service inter-agency guidelines for screening donors of blood, plasma, organs, tissues, and semen for evidence of hepatitis B and hepatitis C. MMWR 1991;40(No. RR-4):1–17. 167. Ridzon R, Gallagher K, Ciesielski C, et al. Simultaneous transmission of human immunodeficiency virus and hepatitis C virus from a needle-stick injury. N Engl J Med 1997;336:919–22. 168. Ciesielski CA, Metler RP. Duration of time between exposure and seroconversion in healthcare workers with occupationally acquired infection with human immunodeficiency virus. Am J Med 1997;102(suppl 5B):115–6. 169. Busch MP, Satten GA. Time course of viremia and antibody seroconversion following human immunodeficiency virus exposure. Am J Med 1997;102(suppl 5B):117–24. 170. Rich JD, Merriman NA, Mylonakis E, et al. Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a case series. Ann Intern Med 1999;130:37–9. 171. Roland ME, Elbeik TA, Martin JN, et al. HIV-1 RNA testing by bDNA and PCR in asymptomatic patients following sexual exposure to HIV [Abstract 776]. In: Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA: Foundation for Retrovirology and Human Health in scientific collaboration with the National Institute of Allergy and Infectious Diseases and CDC, 2000:220. Vol. 50/No. RR-11 MMWR 38

172. Gerberding JL, Henderson DK. Management of occupational exposures to bloodborne pathogens: hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Clin Inf Dis 1992;14:1179–85. 173. Armstrong K, Gorden R, Santorella G. Occupational exposures of health care workers (HCWs) to human immunodeficiency virus (HIV): stress reactions and counseling interventions. Soc Work Health Care 1995;21:61–80. 174. Henry K, Campbell S, Jackson B, et al. Long-term follow-up of health care workers with work- site exposure to human immunodeficiency virus [Letter]. JAMA 1990;263:1765. 175. AIDS/TB Committee of the Society for Healthcare Epidemiology of America. Management of healthcare workers infected with hepatitis B virus, hepatitis C virus, human immunodeficiency virus, or other bloodborne pathogens. Infect Control Hosp Epidemiol 1997;18:349–63. Vol. 50/No. RR-11 MMWR 39 APPENDIX A.

Practice Recommendations for Health-Care Facilities Implementing the U.S. Public Health Service Guidelines for Management of Occupational Exposures to Bloodborne Pathogens

Practice recommendation Implementation checklist All institutions where health-care personnel (HCP) might experience exposures should have a written policy for management of exposures.

Establish a bloodborne pathogen policy. The policy should be based on the U.S. Public Health Service (PHS) guidelines

The policy should be reviewed periodically to ensure that it is consistent with PHS recommendations Health-care facilities (HCF) should provide appropriate training to all personnel on the prevention of and response to occupational exposures

HCF should establish hepatitis B vaccination programs

HCF should establish exposure-reporting Implement management policies systems

HCF should have personnel who can manage an exposure readily available at all hours of the day

HCF should have ready access to postexposure prophylaxis (PEP) for use by exposed personnel as necessary HCF should provide prompt processing of exposed person and source person specimens to guide management of Establish laboratory capacity for occupational exposures bloodborne pathogen testing Testing should be performed with appropriate counseling and consent Vol. 50/No. RR-11 MMWR 40

Practice recommendation Implementation checklist HCF should develop a policy for the selection and use of PEP antiretroviral regimens for HIV exposures within their institution Select and use appropriate PEP regimens Hepatitis B vaccine and HBIG should be available for timely administration

HCF should have access to resources with expertise in the selection and use of PEP HCF should provide counseling for HCP who might need help dealing with the emotional effect of an exposure Provide access to counseling for exposed HCP HCF should provide medication adherence counseling to assist HCP in completing HIV PEP as necessary HCP taking antiretroviral PEP should be monitored periodically for adverse effects Monitor for adverse effects of PEP of PEP through baseline and testing (every 2 weeks) and clinical evaluation HCF should develop a system to encourage exposed HCP to return for follow-up testing Monitor for seroconversion Exposed HCP should be tested for HCV and HIV HCF should develop a system to monitor reporting and management of occupational exposures to ensure timely and appropriate response

Evaluate  exposure reports for completeness and accuracy,  access to care (i.e., the time of exposure to the time of evaluation), Monitor exposure management programs and  laboratory result reporting time Review  exposures to ensure that HCP exposed to sources not infected with bloodborne pathogens do not receive PEP or that PEP is stopped Monitor  completion rates of HBV vaccination and HIV PEP and  completion of exposure follow-up Vol. 50/No. RR-11 MMWR 41 APPENDIX B. Management of Occupational Blood Exposures

Provide immediate care to the exposure site  Wash wounds and skin with soap and water  Flush mucous membranes with water. Determine risk associated with exposure by  type of fluid (e.g., blood, visibly bloody fluid, other potentially infectious fluid or tissue, and concentrated virus) and  type of exposure (i.e., percutaneous injury, mucous membrane or nonintact skin exposure, and bites resulting in blood exposure). Evaluate exposure source  Assess the risk of infection using available information  Test known sources for HBsAg, anti-HCV, and HIV antibody (consider using rapid testing)  For unknown sources, assess risk of exposure to HBV, HCV, or HIV infection  Do not test discarded needles or syringes for virus contamination. Evaluate the exposed person  Assess immune status for HBV infection (i.e., by history of hepatitis B vaccination and vaccine response) Give PEP for exposures posing risk of infection transmission  HBV: See Table 3.  HCV: PEP not recommended  HIV: See Tables 4 and 5 --Initiate PEP as soon as possible, preferably within hours of exposure --Offer pregnancy testing to all women of childbearing age not known to be pregnant --Seek expert consultation if viral resistance is suspected --Administer PEP for 4 weeks if tolerated Perform follow-up testing and provide counseling  Advise exposed persons to seek medical evaluation for any acute illness occurring during follow-up. HBV exposures  Perform follow-up anti-HBs testing in persons who receive hepatitis B vaccine --Test for anti-HBs 1–2 months after last dose of vaccine --Anti-HBs response to vaccine cannot be ascertained if HBIG was received in the previous 3–4 months. HCV exposures  Perform baseline and follow-up testing for anti-HCV and alanine aminotransferase (ALT) 4–6 months after exposures  Perform HCV RNA at 4–6 weeks if earlier diagnosis of HCV infection desired  Confirm repeatedly reactive anti-HCV enzyme immunoassays (EIAs) with supplemental tests. HIV exposures  Perform HIV-antibody testing for at least 6 months postexposure (e.g., at baseline, 6 weeks, 3 months, and 6 months)  Perform HIV antibody testing if illness compatible with an acute retroviral syndrome occurs  Advise exposed persons to use precautions to prevent secondary transmission during the follow-up period  Evaluate exposed persons taking PEP within 72 hours after exposure and monitor for drug toxicity for at least 2 weeks. Vol. 50/No. RR-11 MMWR 42 APPENDIX C. Basic and Expanded HIV Postexposure Prophylaxis Regimens

BASIC REGIMEN  Zidovudine (RETROVIR™; ZDV; AZT) + Lamivudine (EPIVIR™; 3TC); available as COMBIVIR™ --ZDV: 600 mg per day, in two or three divided doses, and --3TC: 150 mg twice daily.

Advantages --ZDV is associated with decreased risk of HIV transmission in the CDC case- control study of occupational HIV infection. --ZDV has been used more than the other drugs for PEP in HCP. --Serious toxicity is rare when used for PEP. --Side effects are predictable and manageable with antimotility and antiemetic agents. --Probably a safe regimen for pregnant HCP. --Can be given as a single tablet (COMBIVIR™) twice daily.

Disadvantages --Side effects are common and might result in low adherence. --Source patient virus might have resistance to this regimen. --Potential for delayed toxicity (oncogenic/teratogenic) is unknown.

ALTERNATE BASIC REGIMENS  Lamivudine (3TC) + Stavudine (ZERIT™; d4T) --3TC: 150 mg twice daily, and --d4T: 40 mg (if body weight is <60 kg, 30 mg twice daily) twice daily.

Advantages --well tolerated in patients with HIV infection, resulting in good adherence, --serious toxicity appears to be rare, and --twice daily dosing might improve adherence.

Disadvantages --Source patient virus might be resistant to this regimen. --Potential for delayed toxicity (oncogenic/teratogenic) is unknown.

 Didanosine (VIDEX™, chewable/dispersable buffered tablet; VIDEX™ EC, delayed- release capsule; ddI) + Stavudine (d4T) --ddI: 400 mg (if body weight is <60 kg, 125 mg twice daily) daily, on an empty stomach. --d4T: 40 mg (if body weight is <60 kg, 30 mg twice daily) twice daily.

Advantages --Likely to be effective against HIV strains from source patients who are taking ZDV and 3TC. Disadvantages --ddl is difficult to administer and unpalatable. --Chewable/dispersable buffered tablet formulation of ddI interferes with absorption of some drugs (e.g., quinolone antibiotics, and indinavir). Vol. 50/No. RR-11 MMWR 43

--Serious toxicity (e.g., neuropathy, pancreatitis, or hepatitis) can occur. Fatal and nonfatal pancreatitis has occurred in HIV-positive, treatment-naive patients. Patients taking ddI and d4T should be carefully assessed and closely monitored for pancreatitis, lactic acidosis, and hepatitis. --Side effects are common; anticipate diarrhea and low adherence. --Potential for delayed toxicity (oncogenic/teratogenic) is unknown.

EXPANDED REGIMEN Basic regimen plus one of the following:  Indinavir (CRIXIVAN™; IDV) --800 mg every 8 hours, on an empty stomach.

Advantages --Potent HIV inhibitor.

Disadvantages --Serious toxicity (e.g., nephrolithiasis) can occur; must take 8 glasses of fluid per day. --Hyperbilirubinemia common; must avoid this drug during late pregnancy. --Requires acid for absorption and cannot be taken simultaneously with ddI in chewable/dispersable buffered tablet formulation (doses must be separated by at least 1 hour). --Concomitant use of astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John’s Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended. --Potential for delayed toxicity (oncogenic/teratogenic) is unknown.

 Nelfinavir (VIRACEPT™; NFV) --750 mg three times daily, with meals or snack, or --1250 mg twice daily, with meals or snack.

Advantages --potent HIV inhibitor, and --twice dosing per day might improve adherence.

Disadvantages --Concomitant use of astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John’s Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended. --Might accelerate the clearance of certain drugs, including oral contraceptives (requiring alternative or additional contraceptive measures for women taking these drugs). --Potential for delayed toxicity (oncogenic/teratogenic) is unknown.

 Efavirenz (SUSTIVA™; EFV) --600 mg daily, at bedtime.

Advantages --Does not require phosphorylation before activation and might be active earlier than other antiretroviral agents (note: this might be only a theoretical advantage of no clinical benefit.) --One dose daily might improve adherence. Vol. 50/No. RR-11 MMWR 44

Disadvantages --Drug is associated with rash (early onset) that can be severe and might rarely progress to Stevens-Johnson syndrome. --Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person. --Nervous system side effects (e.g., dizziness, somnolence, insomnia, and/or abnormal dreaming) are common. Severe psychiatric symptoms are possible (dosing before bedtime might minimize these side effects). --Should not be used during pregnancy because of concerns about teratogenicity. --Concomitant use of astemizole, cisapride, midazolam, triazolam, ergot derivatives, or St. John’s Wort is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or life- threatening adverse events (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). --Potential for oncogenic toxicity is unknown.

 Abacavir (ZIAGEN™; ABC); available as TRIZIVIR™, a combination of ZDV, 3TC, and ABC --300 mg twice daily.

Advantages --potent HIV inhibitor, and --well tolerated in patients with HIV infection.

Disadvantages --Severe hypersensitivity reactions can occur, usually within the first 6 weeks of treatment. --Potential for delayed toxicity (oncogenic/teratogenic) is unknown.

ANTIRETROVIRAL AGENTS FOR USE AS PEP ONLY WITH EXPERT CONSULTATION  Ritonavir (NORVIR™; RTV)

Disadvantages --difficult to take (requires dose escalation), --poor tolerability, and --many drug interactions.

 Saquinavir (FORTOVASE™, soft-gel formulation; SQV)

Disadvantages --Bioavailability is relatively poor, even with new formulation.

 Amprenavir (AGENERASE™; AMP)

Disadvantages --Dosage consists of eight large pills taken twice daily. --Many drug interactions.

 Delavirdine (RESCRIPTOR™; DLV) Vol. 50/No. RR-11 MMWR 45

Disadvantages --Drug is associated with rash (early onset) that can be severe and progress to Stevens Johnson syndrome. --Many drug interactions.  Lopinavir/Ritonavir (KALETRA™) --400/100 mg twice daily.

Advantages --potent HIV inhibitor, and --well tolerated in patients with HIV infection.

Disadvantages --Concomitant use of flecainide, propafenone, astemizole, terfenadine, dihydroergotamine, ergotamine, ergonovine, methylergonovine, rifampin, cisapride, St. John’s Wort, lovastatin, simvastatin, pimozide, midazolam, or triazolam is not recommended because inhibition of the metabolism of these drugs could create the potential for serious and/or life- threatening adverse events (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). --May accelerate the clearance of certain drugs, including oral contraceptives (requiring alternative or additional contraceptive measures for women taking these drugs). --Potential for delayed toxicity (oncogenic/teratogenic) is unknown.

ANTIRETROVIRAL AGENTS GENERALLY NOT RECOMMENDED FOR USE AS PEP

 Nevirapine (VIRAMUNE™; NVP) --200 mg daily for 2 weeks, then 200 mg twice daily.

Disadvantages --Associated with severe hepatotoxicity (including at least one case of liver failure requiring liver transplantation in an exposed person taking PEP), --Associated with rash (early onset) that can be severe and progress to Stevens- Johnson syndrome, --Differentiating between early drug-associated rash and acute seroconversion can be difficult and cause extraordinary concern for the exposed person, and --Concomitant use of St. John’s Wort is not recommended because this might result in suboptimal antiretroviral drug concentrations. Recommendations and Reports Continuing Education Activity Sponsored by CDC

Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis

EXPIRATION — June 29, 2002 You must complete and return the response form electronically or by mail by June 29, 2002, to receive continuing education credit. If you answer all of the questions, you will receive an award letter for 1.75 hours Continuing Medical Education (CME) credit, .15 hour Continuing Education Units (CEUs), or 2.0 hours Continuing Nursing Education (CNE) credit. If you return the form electronically, you will receive educational credit immediately. If you mail the form, you will receive educational credit in approximately 30 days. No fees are charged for participating in this continuing education activity.

INSTRUCTIONS By Internet 1. Read this MMWR (Vol. 50, RR-11), which contains the correct answers to the questions beginning on the next page. 2. Go to the MMWR Continuing Education Internet site at http://www.cdc.gov/mmwr/cme/conted.html 3. Select which exam you want to take and select whether you want to register for CME, CEU, or CNE credit. 4. Fill out and submit the registration form. 5. Select exam questions. To receive continuing education credit, you must answer all of the questions. Questions with more than one correct answer will instruct you to “Indicate all that apply.” 6. Submit your answers no later than June 29, 2002. 7. Immediately print your Certificate of Completion for your records.

By Mail or Fax 1. Read this MMWR (Vol. 50, RR-11), which contains the correct answers to the questions beginning on the next page. 2. Complete all registration information on the response form, including your name, mailing address, phone number, and e-mail address, if available. 3. Indicate whether you are registering for CME, CEU, or CNE credit. 4. Select your answers to the questions, and mark the corresponding letters on the response form. To receive continuing education credit, you must answer all of the questions. Questions with more than one correct answer will instruct you to “Indicate all that apply.” 5. Sign and date the response form or a photocopy of the form and send no later than June 29, 2002, to Fax: 404-639-4198 Mail: MMWR CE Credit Office of Scientific and Health Communications Epidemiology Program Office, MS C-08 Centers for Disease Control and Prevention 1600 Clifton Rd, N.E. Atlanta, GA 30333 6. Your Certificate of Completion will be mailed to you within 30 days.

ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.75 hours in category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards .15 hour Continuing Education Units (CEUs).

Continuing Nursing Education (CNE). This activity for 2.0 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center’s Commission on Accreditation.

GOALS and OBJECTIVES: The MMWR provides recommendations regarding the guidance of clinical practice and policy development related to the management of occupational exposures to blood and bloodborne pathogens, including the appropriate use of postexposure prophylaxis (PEP). Upon completion of this educational activity, the reader should be able to a) describe the management process following an occupational exposure to blood; b) describe the evaluation of the exposure and assessment of the risk for bloodborne pathogen transmission; c) describe appropriate laboratory evaluation of the exposed worker and source person; d) describe appropriate selection and use of PEP; and e) describe the follow-up evaluation and counseling of exposed health-care personnel (HCP).

To receive continuing education credit, please answer all of the following questions. 1. Factors to consider in assessing the need for follow-up after an occupational exposure include A. The type of exposure. B. The type of fluid. C. The bloodborne pathogen infection status of the source. D. The susceptibility of the exposed. E. All of the above. F. None of the above. 2. Which of the following exposures pose a risk for bloodborne pathogen infection? A. A nurse sustains a needlestick while drawing up insulin to administer to a patient with diabetes. B. A lab worker is splashed in the eye with urine from a patient with HIV. C. An operating room technician with chapped and abraded hands notices blood under his/her gloves after assisting in a surgery on a patient with hepatitis C infection. D. While cleaning the bathroom, a housekeeper’s intact skin has contact with feces. 3. Which lab tests should be completed for the exposed person to determine his/her susceptibility to a bloodborne pathogen infection? A. HBsAg. B. HIV p24 antigen. C. HCV RNA. D. All of the above. E. None of the above. 4. Following a percutaneous exposure to HCV-infected blood, what action(s) is/are recommended? A. Test the exposed person for antibody to HCV and alanine aminotransferase (ALT) at the time of the exposure and 4–6 months postexposure. B. Administer one dose of immune globulin within 7 days of the exposure. C. Immediately start PEP with interferon and ribavirin. D. All of the above. E. None of the above. 5. After completing the initial 3-dose vaccine series against HBV, HCP who will have contact with patients or blood and are at ongoing risk for percutaneous injuries should have anti-HBs testing completed A. Every year. B. After any blood exposure. C. 1–2 months after the completion of the vaccine series. D. All of the above. E. None of the above. 6. The type of occupational exposure to HIV-infected blood that poses the greatest risk for infection transmission is A. A percutaneous injury. B. A mucous membrane exposure. C. A bite. D. Skin contact with HIV-infected blood. 7. For which of the following exposures would the use of HIV PEP be recommended? A. A housekeeper sustains a percutaneous injury while emptying a needle box on a pediatric ward with no known cases of HIV infection. B. A nurse has a urine splash to the eye while emptying an AIDS patient’s urinal. C. A resident, after assisting with an emergency insertion of a central venous line into an HIV- infected patient, notices a small tear in his/her glove but does not observe any blood on his/her skin. D. A phlebotomist sustains a percutaneous injury while performing phlebotomy on an HIV- infectedpatient. E. All of the above. 8. Following an exposure to a bloodborne pathogen, what information would be included as part of the postexposure counseling? (Indicate all that apply.) A. HCP exposed to HBV and HCV do no need to take any special precautions to prevent secondary transmission during the follow-up period. B. Modifying an exposed person’s patient care responsibilities is not necessary to prevent transmission to patients after an exposure to HBV, HCV, or HIV. C. HCP who have an HIV exposure for which PEP is not recommended should be informed that the potential side effects and toxicity of taking PEP outweigh the risk of transmission posed by the type of exposure. D. HCP should seek medical evaluation for any acute illness that occurs during the follow-up period. 9. Indicate your work setting. A. State/local health department. B. Other public health setting. C. Hospital clinic/private practice. D. Managed care organization. E. Academic institution. F. Other. 10. Which best describes your professional activities? A. Patient care - emergency/urgent care department. B. Patient care - inpatient. C. Patient care - primary-care clinic or office. D. Laboratory/pharmacy. E. Public health. F. Other. 11. I plan to use these recommendations as the basis for ... (Indicate all that apply.) A. Health-educationmaterials. B. Insurance reimbursement policies. C. Local practice guidelines. D. Public policy. E. Other. 12. Each month, approximately how many patients do you see with occupational exposure? A. None. B. 1–5. C. 6–0. D. 21–50. E. 51–100. F. >100. 13. How much time did you spend reading this report and completing the exam? A. 1–1.5 hours. B. More than 1.5 hours but fewer than 2 hours. C. 2–2.5 hours. D. More than 2.5 hours. 14. After reading this report, I am confident that I can describe the management process following an occupational exposure to blood. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 15. After reading this report, I am confident that I can describe the evaluation of the exposure and assessment of the risk for bloodborne pathogen transmission. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 16. After reading this report, I am confident that I can describe appropriate laboratory evaluation of the exposed worker and source person. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 17. After reading this report, I am confident that I can describe appropriate selection and use of PEP. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree 18. After this report, I am confident that I can describe the follow-up evaluation and counseling of an exposed worker. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 19. The objectives are relevant to the goal of this report. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 20. The tables, boxes, and appendices are useful. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 21. Overall, the presentation of the report enhanced my ability to understand the material. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 22. These recommendations will affect my practice. A. Strongly agree. B. Agree. C. Neither agree nor disagree. D. Disagree. E. Strongly disagree. 23. How did you learn about this continuing education activity? A. Internet. B. Advertisement (e.g., fact sheet, MMWR cover, newsletter, or journal). C. Coworker/supervisor. D. Conference presentation. E. MMWR subscription. F. Other MMWR Response Form for Continuing Education Credit June 29, 2001/Vol. 50/No. RR-11 Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis

To receive continuing education credit, you must 1. provide your contact information; 2. indicate your choice of CME, CEU, or CNE credit; 3. answer all of the test questions; 4. sign and date this form or a photocopy; 5. submit your answer form by June 29, 2002. Failure to complete these items can result in a delay or rejection of your application for continuing education credit.

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